Multiple-component pharmaceutical formulations and methods for their use in treating neuropathology and neurodegeneration caused by traumatic injury

ABSTRACT

Novel two-component formulations, procedures and methods for use in treating neuropathology and neurodegeneration incident to trauma are provided. Two-component formulations of the invention comprise biologically active forms of at least one neurosteroid or neuroactive steroid, such as progesterone or synthetic progestin, and at least one anti-epileptic or anticonvulsant, such as pregabalin. The provided formulations are configured or adapted to prevent or reduce the incidence and severity of neurological damage caused by trauma. Formulations, procedures and methods of the invention advantageously effect both neuroprotective actions to prevent or reduce secondary injuries, and neurotrophic actions to repair and restore cells and tissues affected by the trauma, and are especially useful in treating neurological trauma, such as those caused by sports injuries, chemical weapons, vehicle collisions and improvised explosive devices in combat.

RELATED APPLICATION AND PRIORITY

This Utility patent application claims the priority and benefit ofcommonly owned U.S. Provisional Patent Application Ser. No. 61/750,745of James L. Henry, as filed 9 Jan. 2013, and as entitled “Formulations,Methods And Procedures For Reducing Or Preventing The Development Or TheRisk Of Development Of Neuropathology As A Result Of Traumatic Injury”which provisional patent application is hereby incorporated by referencein its entirety into the present patent application. Also herebyincorporated by reference in their entireties are each of the referencescited herein, as well as those cited in Provisional Patent ApplicationSer. No. 61/750,745.

FIELD OF THE INVENTION

The presently disclosed invention, and the many particular embodimentsof the invention, relate to multiple-component formulations, the use ofsuch formulations, and to methods, procedures and combinations thereofto prevent, eliminate, or reduce, or to reduce the risk of, the damagethat can otherwise lead to numerous types of neuropathology andneurodegeneration as a result of trauma.

BACKGROUND OF THE INVENTION Clinical Context and Terminology

Trauma to neural tissue often leads to injury, dysfunction or death ofcells and tissues, and thus to numerous adverse health conditions anddisabilities. Such trauma includes damage to nerve cells, or to cellsthat support the healthy normal function and survival of nerve cells,and therefore includes damage to tissues that support the healthy, ornormal, function and survival of nerve cells and tissues.

Injury to these cells and tissues typically occurs as a result of twofactors. The first factor is the direct effect of the trauma itself.This is a primary type injury. The second factor results frombiochemical cascades of cellular and metabolic processes that areactivated or triggered directly by the trauma-induced tissue damage ofthe primary injury. The direct, or “primary,” damage (such as physicaldisruption) is not salvageable once it has developed. However, inaccordance with the presently disclosed novel formulations, proceduresand methods, the indirect damage, which is typically considered a“secondary injury”, or “secondary damage”, or “neuropathology”, issalvageable. This secondary injury, by nature of the biochemical andmetabolic pathways governing this injury, can be reduced, ameliorated orprevented by the present therapeutic treatments, interventions andformulations.

In the context of the presently disclosed technology the term “trauma”means a wound, injury or damage to a mammalian body or body part, or acondition resulting from such a wound or injury. In one aspect, thepresently disclosed technology is particularly applicable to a wound,injury or damage that includes, as examples, physical, chemical,metabolic, medical, surgical or any other injury or damage to any tissuenerve or nerve cell, whether in the central nervous system or in theperiphery, as described herein.

In another aspect, the presently disclosed technology is particularlyapplicable to physical trauma induced by, for example but notexclusively, vehicle accidents, workplace accidents, sports injuries andaccidents, falls, burns, radiation, battlefield injuries such as but notexclusive to concussive blast injuries and injuries from landmines orimprovised explosive devices (IED's), penetrating injuries and the likebut can occur as a result of any traumatic event.

The presently disclosed technology is also particularly applicable tochemical trauma induced by, for example but not exclusively, medicationor medication overdose, drug or drug overdose, drug abuse (such asmethylenedioxyamphetamine, or MDMA, and the like), alcohol overdose,stimulant drugs (such as pentylenetetrazol), streptozotocin, carbondioxide poisoning, heavy metals, acrylamide and related chemicals,overexposure to certain environmental chemicals (such as copper) ornatural hazards (such as scorpion venom toxin), herbicides, agriculturalinsecticides (such as lindane), hazardous industrial chemicals,neurotoxin bioterrorism chemicals (such as soman and sarin), radiationbioterrorism chemicals (such as polonium and strontium), and the like.

As an additional advantage, the presently disclosed technology isparticularly applicable to metabolic trauma induced by, as examples butnot exclusively, hypoxia, central nervous system ischemia, peripheralischemia, enteric nervous system ischemia, hypoperfusion of nervetissue, multiple sclerosis, shingles (herpes zoster), diabetes, diabeticshock, stroke, epileptic or other seizure, post-polio syndrome, HIV/AIDSperipheral neuropathic pain, subacute posttraumatic myelopathy, andother effects, syndromes and conditions following some type of trauma tothe body or its nervous system. Metabolic trauma can also include but isnot exclusive to hypoglycemia, hyperglycemia, ischemia, diabetic shock,epilepsy or seizure, hypoperfusion of nerve tissue during cardiacarrest, hypoperfusion in newborns resulting from complications atdelivery, and the like.

The presently disclosed technology is similarly applicable to traumainduced by medical treatment or procedure, for example but notexclusively, injections, inoculation, implants, antibiotics, biologicdrugs, antibodies, chemotherapy (for example but not exclusively withmethotrexate, cisplatin, cytosine arabinose, carmustine, thiotepa amongothers), radiation therapy, immunosuppressants (for example tacrolimus),and the like, or during a medical procedure that can reduce or impedethe blood supply for any period of time, and the like.

Trauma from surgery includes, as examples, laparoscopy, amputation,mastectomy, cesarean section, cardiac surgery, hernia repair,cholecystectomy, joint replacement, thoracotomy, reparative surgery orany case, condition or situation where there is or might be detectableor undetectable cut, wound, injury or damage to nerves, nerve cells,neural support cells or neural support tissues or where long-termoutcome from surgery can include adverse health conditions or disabilityas, for example, with failed back syndrome.

Trauma, or “neurotrauma”, to nerve cells, to neural support cells or toneural support tissues, can be, for example but not exclusively, braininjury that would include traumatic brain injury, central nervous systemischemia, spinal cord injury, enteric nervous system injury, peripheralnerve injury or other type of injury to nerve cells.

Outcomes of traumatic damage to nerve cells or tissues differsignificantly from the outcomes of traumatic damage to non-neuraltissues and cells. Non-neural tissues repair relatively rapidly comparedto nerves or nerve cells, and that repair often results in a damage siterestored to nearly identical condition to the original (pre-trauma)state of the tissue, especially with respect to function. In starkcontrast, trauma to neural tissue, such as nerves, nerve cells or any ofthe neural support cells or neural support tissues, often results inadverse health conditions or outcomes that persist for days, weeks orpermanently. It is this set of disadvantageous characteristics andevents regarding neural tissues to which the present invention isdirected.

The severity and duration of such adverse outcomes resulting from neuraltissue injury and cell death are governed by a balance of restorativeand degenerative processes in those neural cells and tissues. In suchinjured cells and tissues, restorative processes drive cells and tissuestoward recovery and repair, and the restoration of pre-trauma function.During the same period, degenerative processes drive cells and tissuestoward loss of cell integrity and function, and even toward cell death.Effective control of the balance of restorative and degenerativeprocesses following trauma to neural tissue has proven to be difficult.It is noteworthy that this balance is often skewed toward thedegenerative outcomes in neural tissue, such as cell or tissue death,and thus to permanent dysfunction and disability.

Standard medical and therapeutic systems and processes have shown littleeffectiveness in addressing these negative outcomes. There is thereforea significant clinical and societal need for new methods andformulations directed toward the treatment of secondary injury to neuraltissues, such as nerve cells, neural support cells and neural supporttissues that maintain the health and function of nerve cells.

The scope and spirit of the many present invention embodiments aredirected toward addressing this clinical and societal heretoforeunsolved need by promoting natural restorative processes whileinhibiting intrinsic degenerative processes, thereby reducing orpreventing the development, or the risk of development, ofneuropathology and neurodegeneration as a result of traumatic injury.

Neuropathology and Manifestations Thereof

In the context of the disclosure, the terminology “neuropathology”includes neuropathy, neurodegeneration and other effects of trauma onnerve cells, neural support cells and neural support tissues as definedherein. Neuropathology and neurodegeneration following trauma can occurin the brain, brainstem, cerebellum or spinal cord, in the entericnervous system and in peripheral sensory, motor and autonomic nerves.Neuropathology and neurodegeneration are also influenced by events thatimpact neural support cells and neural support tissues, as neuron/glialinteractions are important in brain and spinal cord homeostasis and arevital for survival of neurons in health as well as after brain andspinal cord injury and nerve cells require an adequate supply of oxygenand glucose from the vascular supply, and an adequate removal ofcellular waste products by the vascular supply. As one example,injury-induced loss of glial cells or loss of glial function has beenreported to have a negative outcome on injured neurons.

Brain injury is a major public health issue, inter alia, because it is aleading cause of disability. Brain injury occurs commonly from falls,motor vehicle accidents, sports injuries and accidents, workplaceaccidents, other accidents, and explosions, as well as in warfare, butdamage to the brain can also be inflicted by chemical, surgical,metabolic and other types of trauma as described herein. Repeated minorsymptomatic or asymptomatic concussions and injuries to the brain have acumulative effect that can be expressed as recurring headaches, periodsof short term memory loss, depression, and appear, for example, asdementia pugilistica, posttraumatic stress disorder, chronic traumaticencephalopathy and similar disorders. Brain injury, or neuropathologyand neurodegeneration more broadly, can also be caused, as one example,in patients with cancer who receive cancer drug therapies, which canresult in complications including, among others, posterior reversibleencephalopathy syndrome, cognitive dysfunction, and the like. As anotherexample, therapeutic radiation also can lead to brain injury; whitematter necrosis has been shown to occur at doses of >60Gy, leading tofunctional deficits including impairments in memory, attention andexecutive function, with profound effects on quality of life. Whetherthe numbers are large, as in the case of battlefield brain injury, orsmall, as with falls in the elderly, brain injury can be devastating andlife-changing to the individual.

Central nervous system ischemia is that condition when the blood supplyor circulation to the brain, the brainstem, the cerebellum or the spinalcord is reduced. CNS ischemia may result from any reduction,restriction, interference or slowing of the blood circulation. Centralnervous system ischemia can be focal or global. Cerebral ischemia aloneis one of the leading causes of long-term disability; a recent reviewreports an estimated 700,000 cases of ischemic stroke in the US eachyear. When the normal blood supply to central nervous system tissue isoccluded, or blocked, by a clot this is called a thrombotic stroke. Incases where a clot has been dislodged or broken off elsewhere in thecirculation this is called an embolic stroke, such as the cerebralinjury that occurs, for example, during surgical transcatheter aorticvalve implantation. Brainstem, or cerebellar or spinal ischemia canresult from surgical procedures, for example by aortic cross clampingduring cardiac surgery, or as a result of hypoperfusion during cardiacarrest, or in newborns, as a result of temporary or prolongedhypoperfusion due to complications at delivery. Whether the numbers arelarge, as in the case of stroke, or small, as in the case of embolismfrom transcatheter aortic valve implantation, cerebral ischemia can havedevastating and life-changing outcomes for the individual.

Spinal cord injury has a severe impact on individual victims, on thehealthcare system and on the economy, as evidenced from epidemiologicalstudies and professional reports. A recent systematic review indicatedthat an estimated 40 million people worldwide incur a spinal cord injuryevery year, and that most are young men. Of the new cases of spinal cordinjury each year in the U.S., it has been reported that motor vehiclecrashes account for 40% of spinal injuries, falls account for 28% andacts of violence such as gunshot or other wounds account for 15%. Sportsinjuries account for 8%, with another 9% of unreported or unknowncauses. Whether the numbers are large, as in the case of vehicularaccidents, or small, as in the case of many of the unreported cases,spinal cord injury can have a damaging and life-changing outcome for theindividual.

The enteric nervous system is vulnerable to trauma, including ischemia,chemical and inflammatory trauma, physical trauma such as puncturewounds, parasitic and amoeboid infection, and radiation, among othertypes of trauma. Many of the adverse health conditions and disabilitythat result from enteric nervous system injury are due to secondaryinjury processes. As examples, chemotherapy and radiation therapy canlead to dysfunction and even cell death of neurons in thegastrointestinal tract. Bariatric surgery is associated with a number ofneurological complications attributed to effector mechanisms besideschanges in nutritional state, and may be associated with peripheralneuropathy, myelopathy, radiculoneuropathy and even encephalopathy. Manytypes of parasitic and amoeboid infiltrations, including salmonella,rotavirus, and many other bacterial, viral, and protozoan organisms,selectively produce neurotoxicity to enteric neuron cells, neuralsupport cells and neural support tissues. Secondary injury to theenteric nervous system can have disabling and life-changing effects onthe individual victim.

Neuropathology or neuropathy of peripheral nerves results in a myriad ofadverse health conditions and disability. Neuropathic pain is perhapsthe best documented, largely because of the enormous impact of chronicneuropathic pain on individuals and the fact that it tends to berefractory to medical treatment. However, other outcomes of secondaryinjury to peripheral nerves can be similarly devastating, including, interms of sensory disturbance, numbness, dysesthesia (an unpleasantabnormal sensation, whether spontaneous or evoked), paresthesia (anabnormal sensation, such as tingling, whether spontaneous or evoked),hypoesthesia (decreased sensitivity to stimulation, including thespecial senses) and loss of proprioception (contributing to altered gaitand to falls). In terms of motor control, peripheral neuropathy can leadto weakness, loss of movement, loss of corrective motor control and lossof muscle mass. Neuropathy of the autonomic nervous system can manifestas orthostatic hypotension, dysautonomia, altered sudomotor function,and the like. Whether the numbers are large, as those resulting from caraccidents, or small, such as those resulting from laparoscopic surgery,the result of peripheral nerve injury can be a future of constantburning, debilitating neuropathic pain and any of these other adversehealth conditions and disabilities described herein.

Mechanisms of Secondary Injury

Secondary injury is triggered immediately or within hours, days, weeks,or even months, of the primary injury and can continue and progress overa prolonged period of time over a temporal continuum. This secondaryinjury is caused or brought about by cascades of parallel as well asconsecutive pathogenic processes initiated at the moment of the trauma,often or usually with delayed clinical presentation. Secondary injury isthe result of cellular, metabolic and neurochemical processes that aretriggered by a primary injury but that continue over the hours, days,weeks and even months following trauma.

In addition to any physical damage, trauma also compromises the normalsupply of oxygen and glucose to the nervous system. In turn, this causesa loss of ionic balance. These typically occur within several minutes ofa primary injury.

Nerve cells do not store alternate sources of energy for cellularmetabolism and therefore intracellular stores of adenosine triphosphate(ATP), the source of cellular energy, become rapidly depleted. Oxygen isrequired to generate sufficient ATP by oxidative phosphorylation. Inparticular, the enzyme, sodium/potassium ATPase, in the membrane ofnerve cells is estimated to consume 70% of the energy supplied. ATPasemaintains the sodium/potassium pump that maintains high intracellularpotassium and low intracellular sodium. Among other actions, ATPdepletion leads to multiple cascades of progressive metabolic andbiochemical processes, each of which follows a specific time course,including release of toxic levels of excitatory amino acids, ionicimbalance and acidotoxicity, oxidative stress, nitrative stress,inflammation, apoptosis, nerve terminal depolarization and necrosis. Alllead to cell death, including death of nerve cells, neural support cellsand neural support tissues. Endothelial cells comprise the walls of thevasculature and their death can lead to subsequent loss of integrity ofvessel wall, infiltration of degradative chemicals and immune cells intoneural tissue, as well as bleeding into the extravascular space.

When ATP is no longer available, the membrane polarization is lost andintracellularly stored transmitters exit along their concentrationgradient. In particular, the excitatory amino acid transmitter,glutamate, is released at toxic levels, creating excitotoxicity. Amongthe receptors upon which glutamate acts is the N-methyl-D-aspartate(NMDA) receptor. Activation of this receptor leads to furtherdepolarization through influx of sodium as well as calcium into thecell. Increased intracellular calcium leads to a further calcium releasefrom intracellular stores.

There is also a calcium pump in the neuron cell membrane that normallymaintains physiologically appropriate levels of low intracellularcalcium. A calcium ATPase in neuronal cell membranes governs thiscalcium pump. When the calcium pump ceases due to insufficient ATP,intracellular calcium rises even further. As a result of the influx ofcalcium through the NMDA receptor as well as by loss of the calcium pumpcombined with the release of intracellular calcium there is a massiveactivation of calcium-dependent proteases, lipases and DNAses, causingcells to die by their own catabolism.

Oxidative and nitrative stress spread from an injury zone intosurrounding and even remote brain areas. Oxidative and nitrative stressare linked to activation of poly(ADP-ribose)polymerase, which, at highlevels, impairs anaerobic glycolysis and mitochondrial respiration,leading to further exhaustion of ATP, energy failure and cell death.

Secondary injury can progress to nerve cells, neural support cells andneural support tissues beyond the locus of the primary injury and caninclude even areas remote from the site of this primary injury, whetherin the central nervous system, the enteric nervous system or theperipheral nervous system. Thus, secondary injury can progress over aspatial continuum.

Secondary injury thus spreads both temporally and spatially. Thenegative sequelae may not manifest for weeks, months or years; suicidein athletes and soldiers years after trauma is one example. However, theoptimal time to treat is as soon as possible or even before, around thetime of trauma as described herein. Much of the neuropathology andneurodegeneration that are allowed to develop after the first few daysmay be refractory to any later medical treatment.

SUMMARY OF THE INVENTION Overview of the Invention

The presently disclosed many embodiments of the invention includeformulations, methods, procedures and means for treating anyneuropathological condition that is caused, at least partially, bytrauma of any kind and involves endogenous processes or biosynthetic andmetabolic pathways that govern, regulate or influence the health orfunction of nerves or nerve cells, or cells or tissues upon which nervesor nerve cells depend to maintain health and function. Conditions oftrauma are known to activate or trigger such processes and pathways thatprotect or restore health of nerves and nerve cells, as well as suchprocesses and pathways that lead to loss of function, further damage andeven cell death of nerves, nerve cells, neural support cells and neuralsupport tissues. It is the balance of these restorative versusdegenerative processes and pathways that governs and determinesdisability outcome.

Anticonvulsant/antiepileptic compounds suitable for use as components ofinvention embodiments include, but not exclusively, one or more from thegroup comprising gabapentin, pregabalin, barbiturates (such asphenobarbital, methylphenobarbital, metharbital, barbexaclone and othercentral nervous system depressants), benzodiazepines (such as clozepam,clonazepam, chlorazepate, diazepam, midazolam, lorazepam, and otherhypnotic, anxiolytic, anticonvulsant, amnesic compounds), bromides (suchas potassium bromide,) carbamates (such as felbamate, fluorofelbamate),carboxamides (such as carbamazepine, oxcarbazepeine, eslicarbazepineacetate), fatty acids (such as valproic acid, sodium valproate,divalproex sodium, vigabatrin, progabide, sec-butyl-propylacetamide),fructose derivatives (such as topiramate), hydantoins (such as ethotoin,phenyloin, mephenyloin, fosphentoin), oxazolidinediones (such asparamethadione, trimethadione, ethadione), propionates (such asbeclamide), pyrimidinediones (such as primidone), pyrrolidines (such asrivaracetam, levetiracetam, seletracetam), succinimides (such asethosuximide, phensuximide, mesuximide), sulfonamides (such asacetazolamide, sultiame, methazolamide, zonisamide), triazines (such aslamotrigine), ureas (such as pheneturide, phenacemide) and valproyamides(such as valpromide, valoctamide) and others known and unknown, as wellas any homolog or derivative or compound acting on or through areceptor, an enzyme or other mechanism upon which ananticonvulsive/antiepileptic can act, as well as any compound acting onor through mechanisms that would modify or affect in any way pathways orprocesses affected by one or more anticonvulsant/antiepilepticcompounds, as well as any related slow-release compound.

Neurosteroid/neuroactive steroid compounds suitable for use ascomponents of invention embodiments include, but not exclusively, one ormore from the group comprising progesterone, progesterone prodrugs,progesterone derivatives, progesterone analogs, and other progesteronecompounds such as but not exclusive to medroxyprogesterone acetate,megestrol acetate, 17a-hydroxyprogesterone, 5a-dihydroxyprogesterone,3a,5a-trihydroxyprogesterone, 14b-hydroxy progesterone,17α-hydroxyprogesterone caproate,16-methyl-17-benzoyloxypregnen-4-en-3,20-dione,hydroxyprogesterone-3-O-carboxymethyloxime,21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone,17-p-bromopheny-lcarbamoyloxypregn-4-ene-3,20-dione,17-phenylcarbamoyl-oxypregn-4-ene-3,20-dione, 4-pregnene-3,20-dione,6,19-methanoprogesterone, 16,17-cyclohexano-4,5-dihydroprogesterone,nepapakistamine, vaganine D, Crinone, 18-oxo-18-vinylprogesterone,16,17-cyclopropanoprogesterone, caproxyprogesterone,21-hydroxy-6,19-oxidoprogesterone,17-acetoxy-9-fluoro-6-methylprogesterone, ZK 136798,3,17-dihydroxy-7-(4-methoxyphenyl)-androst-5-ene, 3,17-diacetate,progesterone-11HS-horseradish peroxidase,21-hydroxy-11,19-oxidopregn-4-ene-3,20-dione,21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione, 4-cyanoprogesterone,11,19-oxidoprogesterone, 6-fluoroprogesterone,2-hydroxy-4-pregnene-3,20-dione, progesterone-3-(O-carboxymethyloxime)-horseradish peroxidase, progesterone-11-hemisuccinyl-bovine serumalbumin, pentarane B, pentarane A, progesterone 6-hemimaleate,progesterone 6-hemisuccinate, 7-(carboxyethylthio)progesterone,progesterone 3-(O-carboxymethyl)oxime-bovine serum albumin,18-ethynylprogesterone, 18-vinylprogesterone,6-methylprogesteron-17-pivalate, progesterone-11-bovine serum albumin,allylestriol, progesterone-3-ethanolimine,3,20-dioxopregn-4-ene-18′-carboxaldehyde cyclic18′-(1,2-ethandiylmercaptal), 18-ethylenedithioprogesterone,17-acetoxy-6,16-dimethylene-4-pregnene-3,20-dione,17-hydroxy-6-dehydroprogesterone,2′-methyl-16,17-cyclohexaneprogesterone, 21,21-dichloroprogesterone,hydroxyprogesterone hemisuccinate bovine serum albumintetramethylrhodamine isothiocyanate,11-progesteryl-2-carboxymethyltyramine-4-(10-methyl)acridinium-9-carboxylate,progesterone 12-succinyltyrosine methyl ester, progesterone11-succinyltyrosine methyl ester,1′-progesteryl-2-succinoyltyramine-4-(10-methyl)acridinium-9-carboxylate,2-hydroxymethyleneprogesterone, 2-cyanoprogesterone,17-(phenylseleno)progesterone, 21-(phenylseleno)progesterone and othersknown and unknown, and include other neurosteroids or neuroactivesteroids such as, but not exclusive to prednisolone, methylprednisolone,alphaxolone, alphadolone, hydroxydone, minaxolone, ganaxolone,deoxycorticosterone, 3 alpha-hydroxy-5-alpha-pregnan-one(allopregnanolone), 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one(allotetrahydro), as well as metabolites of neurosteroids andneuroactive steroids, and including any corticoid, glucocorticoid,estrogen compound or any such compound acting on or through aprogesterone, corticosteroid, glucocorticoid, estrogen or otherneurosteroid receptor or through any other mechanism upon whichprogesterone, a corticosteroid, a glucocorticoid, an estrogen or otherneurosteroid does or can act, as well as any homolog or derivative orcompound acting on or through mechanisms that would modify, modulate oraffect in any way pathways or processes affected by progesterone,estrogen or any neurosteroid, as well as any related slow-releasecompound.

NK-1 receptor antagonist compounds suitable for use as components ofinvention embodiments include, but not exclusively, any biologicallyactive compound of one or more from the group comprising aprepitant,fosaprepitant, casopitant, maropitant, vestipitant, CP-99,994,CP-122,721, MK 869, LY 303870, RPR 67580, RPR 100893, L 758298, L365260, L 733060, GR 205171, CGP 49823, CJ 11974, and others known andunknown, and any compound acting on or through the NK-1 receptor or anyother mechanism that involves activation or involvement of the NK-1receptor or its synthesis, and other chemical entities known andunknown, including any ligand or compound acting on or through an NK-1receptor or other mechanism upon which substance P, an endogenous ligandfor the NK-1 receptor, does or can act, as well as any compound actingon or through mechanisms that would modify or affect in any way pathwaysor processes affected by substance P or the NK-1 receptor, as well asany related slow-release compound. Further, in view of the evidence thatsome ligands and compounds can act through or by NK-2 or NK-3 receptors,any ligand or homolog or derivative or compound acting on or through anNK-1 or NK-2 or NK-3 receptor, including receptor isoforms, or relatedmechanism as well as any ligand that occupies, activates or deactivatesthese receptors, is included in the presently disclosed technology.

Lithium-related/lithium-containing compounds suitable for use ascomponents of invention embodiments include, but not exclusively, anybiologically active compound of one or more from the group comprisinglithium citrate, lithium carbonate, lithium chloride, lithium bromatumand others known and unknown, as well as any compound acting on orthrough a lithium receptor or other mechanism upon which lithium does orcan act, as well as any homolog or derivative or compound acting on orthrough mechanisms that would modify or affect in any way pathways orprocesses affected by lithium, as well as any related slow-releasecompound.

Numerous compounds can be administered to a subject in any combinationor permutation of these classes of compound to practice this inventionaimed to reduce or prevent the development or the risk of development ofneuropathology as a result of traumatic injury to a subject byadministering to a subject in need thereof a multiplicity of compoundsby such combinations of any two, any three or any four compounds fromthe classes of compounds comprising anticonvulsants/antiepileptics,neurosteroids/neuroactive steroids, NK-1 receptor antagonists andlithium-related/lithium-containing compounds. These combinations ofabove said compounds can be given by various routes of administration totreat any injury or damage that has resulted, will result or may resultfrom trauma, and that injury or damage can be to any nerve cell or nervecells, to any neural support cell as described herein, or to any neuralsupport tissue as described herein. Injury or damage can be to thebrain, the brain stem, the cerebellum, the spinal cord, the entericnervous system and the peripheral nervous system or any other nervecell. A subject in need of invention embodiments can be an individualwho is at risk of injury or damage, an individual who is about toexperience an event that has the potential to cause traumatic damage orinjury, or an individual who has experienced a trauma as describedherein.

Of the many variations and permutations of the multiple componentformulations of the invention are two-component formulations. Includedin the many two-component formulations of the invention are formulationsadapted for the prevention of the development of neuropathology andneurodegeneration, or for the amelioration of the effects caused bytrauma to a subject, the formulations comprising two biologically activecompounds in amounts that are pharmaceutically effective for eachcompound, respectively, when administered in combination with the otherbiologically active compound. Such formulations comprise apharmaceutically effective amount of: A. at least one biologicallyactive compound from the group comprising anticonvulsants andantiepileptics; and B. at least one biologically active compound fromthe group comprising neurosteroids and neuroactive steroids; and whereinthe formulation is in a form and a dosage with respect to each of itscomponents such that it is adapted and arranged for administration to amammal in need thereof, such that the development, or the risk ofdevelopment, of neuropathology and neurodegeneration is reduced,lessened, attenuated or prevented.

In some preferred embodiments, the component chosen from the group ofanticonvulsants and antiepileptics is at least one form of pregabalin,and the component chosen from the group comprising neurosteroids andneuroactive steroids is at least one form of progesterone or syntheticprogestin.

In some preferred embodiments, the component chosen from the group ofanticonvulsants and antiepileptics is at least one form of gabapentin,and the component chosen from the group comprising neurosteroids andneuroactive steroids is at least one form of progesterone or syntheticprogestin.

Particular compounds that comprise the formulation embodiments are anytwo of an anticonvulsant/antiepileptic/antiepileptic and aneurosteroid/neuroactive steroid or an analog, and these may beadministered to or given to a subject in need in any combination orsequence. In some preferred embodiments of the invention theanticonvulsant/antiepileptic can be pregabalin and theneurosteroid/neuroactive steroid can be progesterone or syntheticprogestin.

Particular compounds that comprise the formulation embodiments are anytwo of an anticonvulsant/antiepileptic/antiepileptic and aneurosteroid/neuroactive steroid or an analog, and these may beadministered to or given to a subject in need in any combination orsequence. In some preferred embodiments of the invention theanticonvulsant/antiepileptic can be pregabalin and theneurosteroid/neuroactive steroid can be progesterone or syntheticprogestin.

Particular compounds that comprise the formulation embodiments are anytwo of an anticonvulsant/antiepileptic/antiepileptic and aneurosteroid/neuroactive steroid or an analog, and these may beadministered to or given to a subject in need in any combination orsequence. In some preferred embodiments of the invention theanticonvulsant/antiepileptic can be gabapentin and theneurosteroid/neuroactive steroid can be progesterone or syntheticprogestin.

As one of ordinary skill in the art will comprehend, appropriate dosagesof compounds according to the various embodiments of the invention canvary widely depending, inter alia, upon the type of trauma or conditionto be treated, the route of treatment, the subject mammal, the sequelaeof mechanisms and processes to be controlled, the compounds involved,the number of biologically active compounds involved, and the like. In asimilar manner, dosage ranges can vary greatly. For example in two-drugformulations, between 10 nanograms and 60 grams of each of thebiologically active components per kilogram of body weight of theindividual mammal. Thus, some typical ranges for the amount ofpregabalin would, for example, include 0.5 to 2,400 mg as an acceptablerange, 15 to 1,200 mg as a preferable range, 25 to 600 mg as a morepreferable range and 50 to 150 mg as a most preferable range. Sometypical ranges for the amount of progesterone or synthetic progestinwould, for example, include 0.05 to 1,200 mg as an acceptable range, 5to 600 mg as a preferable range, 50 to 450 mg as a more preferable rangeand 100 to 300 mg as a most preferable range. As a person of skill inthe art will understand, respective dosages would be arranged andadapted depending on the need, the individual, the severity of thetrauma, the response to administration of the formulation, the time totreatment before or after a traumatic event, the situation, whether inthe field or in a hospital, and the like.

As one of ordinary skill in the art will comprehend, appropriate dosagesof compounds according to the various embodiments of the invention canvary widely depending, inter alia, upon the type of trauma or conditionto be treated, the route of treatment, the subject mammal, the sequelaeof mechanisms and processes to be controlled, the compounds involved,the number of biologically active compounds involved, and the like. In asimilar manner, dosage ranges can vary greatly. For example in two-drugformulations, between 10 nanograms and 60 grams of each of thebiologically active components per kilogram of body weight of theindividual mammal. Thus, some typical ranges for the amount ofgabapentin would, for example, include 5 to 9,600 mg as an acceptablerange, 50 to 4,800 mg as a preferable range, 100 to 2,400 mg as a morepreferable range and 200 to 600 mg as a most preferable range. Sometypical ranges for the amount of progesterone or synthetic progestinwould, for example, include 0.05 to 1,200 mg as an acceptable range, 5to 600 mg as a preferable range, 50 to 450 mg as amore preferable rangeand 100 to 300 mg as a most preferable range. As a person of skill inthe art will understand, respective dosages would be arranged andadapted depending on the need, the individual, the severity of thetrauma, the response to administration of the formulation, the time totreatment before or after a traumatic event, the situation, whether inthe field or in a hospital, and the like.

Of the many variations and permutations of the multiple componentformulations of the invention are three-component formulations. Includedin the many three-component formulations of the invention areformulations adapted for the prevention of the development ofneuropathology and neurodegeneration, or for the amelioration of theeffects caused by trauma to a subject, the formulations comprising threebiologically active compounds in amounts that are pharmaceuticallyeffective for each compound, respectively, when administered incombination with two other biologically active compounds of theformulation. Such formulations comprise a pharmaceutically effectiveamount of: A. at least one biologically active compound from the groupcomprising anticonvulsants and antiepileptics; B. at least onebiologically active compound from the group comprising neurosteroids andneuroactive steroids; and C. at least one biologically active compoundfrom the group comprising lithium-containing and lithium-relatedcompounds; and wherein the formulation is in a form and a dosage withrespect to each of its components such that it is adapted and arrangedfor administration to a mammal in need thereof, such that thedevelopment, or the risk of development, of neuropathology andneurodegeneration is reduced, lessened, attenuated or prevented.

In some preferred embodiments, the component chosen from the group ofanticonvulsants and antiepileptics is at least one form of pregabalain,the component chosen from the group comprising neurosteroids andneuroactive steroids is at least one form of progesterone or syntheticprogestin and the component chosen from the group comprisinglithium-containing and lithium-related compounds is lithium carbonate.

In some preferred embodiments, the component chosen from the group ofanticonvulsants and antiepileptics is at least one form of gabapentin,the component chosen from the group comprising neurosteroids andneuroactive steroids is at least one form of progesterone or syntheticprogestin and the component chosen from the group comprisinglithium-containing and lithium-related compounds is lithium carbonate.

Particular compounds that comprise the formulation embodiments are anythree of an anticonvulsant/antiepileptic/antiepileptic, aneurosteroid/neuroactive steroid and alithium-containing/lithium-related compound or an analog, and these maybe administered to or given to a subject in need in any combination orsequence. In some preferred embodiments of the invention theanticonvulsant/antiepileptic can be pregabalin, theneurosteroid/neuroactive steroid can be progesterone or syntheticprogestin and the lithium-containing/lithium-related compound is lithiumcarbonate.

Particular compounds that comprise the formulation embodiments are anythree of an anticonvulsant/antiepileptic/antiepileptic, aneurosteroid/neuroactive steroid and alithium-containing/lithium-related compound or an analog, and these maybe administered to or given to a subject in need in any combination orsequence. In some preferred embodiments of the invention theanticonvulsant/antiepileptic can be gabapentin, theneurosteroid/neuroactive steroid can be progesterone or syntheticprogestin and the lithium-containing/lithium-related compound is lithiumcarbonate.

As one of ordinary skill in the art will comprehend, appropriate dosagesof compounds according to the various embodiments of the invention canvary widely depending, inter glia, upon the type of trauma or conditionto be treated, the route of treatment, the subject mammal, the sequelaeof mechanisms and processes to be controlled, the compounds involved,the number of biologically active compounds involved, and the like. In asimilar manner, dosage ranges can vary greatly. For example inthree-drug formulations, between 10 nanograms and 60 grams of each ofthe biologically active components per kilogram of body weight of theindividual mammal. Thus, some typical ranges for the amount ofpregabalin would, for example, include 0.5 to 2,400 mg as an acceptablerange, 15 to 1,200 mg as a preferable range, 25 to 600 mg as a morepreferable range and 50 to 150 mg as a most preferable range. Sometypical ranges for the amount of progesterone or synthetic progestinwould, for example, include 0.05 to 1,200 mg as an acceptable range, 5to 600 mg as a preferable range, 50 to 450 mg as a more preferable rangeand 100 to 300 mg as a most preferable range. Some typical ranges forthe amount of lithium, for example lithium carbonate, would, forexample, include 0.5 to 3,600 mg as an acceptable range, 30 to 1,800 mgas a preferable range, 100 to 900 mg as a more preferable range and 200to 600 mg as a most preferable range. As a person of skill in the artwill understand, respective dosages would be arranged and adapteddepending on the need, the individual, the severity of the trauma, theresponse to administration of the formulation, the time to treatmentbefore or after a traumatic event, the situation, whether in the fieldor in a hospital, and the like.

As one of ordinary skill in the art will comprehend, appropriate dosagesof compounds according to the various embodiments of the invention canvary widely depending, inter alia, upon the type of trauma or conditionto be treated, the route of treatment, the subject mammal, the sequelaeof mechanisms and processes to be controlled, the compounds involved,the number of biologically active compounds involved, and the like. In asimilar manner, dosage ranges can vary greatly. For example inthree-drug formulations, between 10 nanograms and 60 grams of each ofthe biologically active components per kilogram of body weight of theindividual mammal. Thus, some typical ranges for the amount ofgabapentin would, for example, include 5 to 9,600 mg as an acceptablerange, 50 to 4,800 mg as a preferable range, 100 to 2,400 mg as a morepreferable range and 200 to 600 mg as a most preferable range. Sometypical ranges for the amount of progesterone or synthetic progestinwould, for example, include 0.05 to 1,200 mg as an acceptable range, 5to 600 mg as a preferable range, 50 to 450 mg as a more preferable rangeand 100 to 300 mg as a most preferable range. Some typical ranges forthe amount of lithium, for example lithium carbonate, would, forexample, include 0.5 to 3,600 mg as an acceptable range, 30 to 1,800 mgas a preferable range, 100 to 900 mg as a more preferable range and 200to 600 mg as a most preferable range. As a person of skill in the artwill understand, respective dosages would be arranged and adapteddepending on the need, the individual, the severity of the trauma, theresponse to administration of the formulation, the time to treatmentbefore or after a traumatic event, the situation, whether in the fieldor in a hospital, and the like.

Of the many variations and permutations of the multiple componentformulations of the invention are four-component formulations. Includedin the many four-component formulations of the invention areformulations adapted for the prevention of the development ofneuropathology and neurodegeneration, or for the amelioration of theeffects caused by trauma to a subject, the formulations comprising fourbiologically active compounds in amounts that are pharmaceuticallyeffective for each compound, respectively, when administered incombination with three other biologically active compounds of theformulation. Such formulations comprise a pharmaceutically effectiveamount of: A. at least one biologically active compound from the groupcomprising anticonvulsants and antiepileptics; B. at least onebiologically active compound from the group comprising neurosteroids andneuroactive steroids; C. at least one biologically active compound fromthe group comprising lithium-containing and lithium-related compounds;and D. at least one biologically active compound from the groupcomprising NK-1 receptor antagonists; and wherein the formulation is ina form and a dosage with respect to each of its components such that itis adapted and arranged for administration to a mammal in need thereof,such that the development, or the risk of development, of neuropathologyand neurodegeneration is reduced, lessened, attenuated or prevented.

In some preferred embodiments, the component chosen from the group ofanticonvulsants and antiepileptics is at least one form of pregabalin,the component chosen from the group comprising neurosteroids andneuroactive steroids is at least one form of progesterone or syntheticprogestin, the component chosen from the group comprisinglithium-containing and lithium-related compounds is lithium carbonateand the component chosen from the group comprising NK-1 receptorantagonists is aprepitant.

In some preferred embodiments, the component chosen from the group ofanticonvulsants and antiepileptics is at least one form of gabapentin,the component chosen from the group comprising neurosteroids andneuroactive steroids is at least one form of progesterone or syntheticprogestin, the component chosen from the group comprisinglithium-containing and lithium-related compounds is lithium carbonateand the component chosen from the group comprising NK-1 receptorantagonists is aprepitant.

Particular compounds that comprise the formulation embodiments are anythree of an anticonvulsant/antiepileptic/antiepileptic, aneurosteroid/neuroactive steroid and alithium-containing/lithium-related compound or an analog, and these maybe administered to or given to a subject in need in any combination orsequence. In some preferred embodiments of the invention theanticonvulsant/antiepileptic can be pregabalin, theneurosteroid/neuroactive steroid can be progesterone or syntheticprogestin, the lithium-containing/lithium-related compound can belithium carbonate and the NK-1 receptor antagonist can be aprepitant.

Particular compounds that comprise the formulation embodiments are anythree of an anticonvulsant/antiepileptic/antiepileptic, aneurosteroid/neuroactive steroid and alithium-containing/lithium-related compound or an analog, and these maybe administered to or given to a subject in need in any combination orsequence. In some preferred embodiments of the invention theanticonvulsant/antiepileptic can be gabapentin, theneurosteroid/neuroactive steroid can be progesterone or syntheticprogestin, the lithium-containing/lithium-related compound can belithium carbonate and the NK-1 receptor antagonist can be aprepitant.

As one of ordinary skill in the art will comprehend, appropriate dosagesof compounds according to the various embodiments of the invention canvary widely depending, inter alia, upon the type of trauma or conditionto be treated, the route of treatment, the subject mammal, the sequelaeof mechanisms and processes to be controlled, the compounds involved,the number of biologically active compounds involved, and the like. In asimilar manner, dosage ranges can vary greatly. For example in four-drugformulations, between 10 nanograms and 60 grams of each of thebiologically active components per kilogram of body weight of theindividual mammal. Thus, some typical ranges for the amount ofpregabalin would, for example, include 0.5 to 2,400 mg as an acceptablerange, 15 to 1,200 mg as a preferable range, 25 to 600 mg as a morepreferable range and 50 to 150 mg as a most preferable range. Sometypical ranges for the amount of progesterone or synthetic progestinwould, for example, include 0.05 to 1,200 mg as an acceptable range, 5to 600 mg as a preferable range, 50 to 450 mg as a more preferable rangeand 100 to 300 mg as a most preferable range. Some typical ranges forthe amount of lithium, for example lithium carbonate, would, forexample, include 0.5 to 3,600 mg as an acceptable range, 30 to 1,800 mgas a preferable range, 100 to 900 mg as a more preferable range and 200to 600 mg as a most preferable range. Some typical ranges for the amountof aprepitant would, for example, include 0.05 to about 750 mg as anacceptable range, 5 to about 375 mg as a preferable range, 20 to about250 mg as a more preferable range and 40 to about 120 mg as a mostpreferable range. As a person of skill in the art will understand,respective dosages would be arranged and adapted depending on the need,the individual, the severity of the trauma, the response toadministration of the formulation, the time to treatment before or aftera traumatic event, the situation, whether in the field or in a hospital,and the like.

As one of ordinary skill in the art will comprehend, appropriate dosagesof compounds according to the various embodiments of the invention canvary widely depending, inter alia, upon the type of trauma or conditionto be treated, the route of treatment, the subject mammal, the sequelaeof mechanisms and processes to be controlled, the compounds involved,the number of biologically active compounds involved, and the like. In asimilar manner, dosage ranges can vary greatly. For example in four-drugformulations, between 10 nanograms and 60 grams of each of thebiologically active components per kilogram of body weight of theindividual mammal. Thus, some typical ranges for the amount ofgabapentin would, for example, include 5 to 9,600 mg as an acceptablerange, 50 to 4,800 mg as a preferable range, 100 to 2,400 mg as a morepreferable range and 200 to 600 mg as a most preferable range. Sometypical ranges for the amount of progesterone or synthetic progestinwould, for example, include 0.05 to 1,200 mg as an acceptable range, 5to 600 mg as a preferable range, 50 to 450 mg as a more preferable rangeand 100 to 300 mg as a most preferable range. Some typical ranges forthe amount of lithium, for example lithium carbonate, would, forexample, include 0.5 to 3,600 mg as an acceptable range, 30 to 1,800 mgas a preferable range, 100 to 900 mg as a more preferable range and 200to 600 mg as a most preferable range. Some typical ranges for the amountof aprepitant would, for example, include 0.05 to about 750 mg as anacceptable range, 5 to about 375 mg as a preferable range, 20 to about250 mg as a more preferable range and 40 to about 120 mg as a mostpreferable range. As a person of skill in the art will understand,respective dosages would be arranged and adapted depending on the need,the individual, the severity of the trauma, the response toadministration of the formulation, the time to treatment before or aftera traumatic event, the situation, whether in the field or in a hospital,and the like.

An analog is a compound that has similar properties and can be amodification of the original drug or enhances the availability of thedrug or provides a slow release, a delayed release or a controlledrelease of the drug for the target but still modifies the pathwaysimilar to the parent compound. As a person having ordinary skill in theart will appreciate, any formulations of compounds that promote orinhibit endogenous processes that are activated by trauma and that areinvolved in the repair or in the injury to nerves or nerve cells arewithin the spirit and scope of the presently disclosed inventionembodiments.

In the context of the presently disclosed technology the term“formulation” means a combination or mixture of pharmaceutically activeor effective chemical entities in respective pharmaceutically effectivedoses, to create a desired end multi-drug product, in such a form thatit can be safely administered to, given to, or taken by, a subject, andmay include other ingredients or substances. Examples of such otheringredients or substances include, as examples, but not limited to,excipients, buffers, penetration enhancers, stabilizers, absorptionenhancers and carriers.

Further, chemical entities in the formulations of the presentlydisclosed technology can include any pro-drug, derivative, metabolite,analog, salt or any other form including natural, standard or slow-,delayed-, sequential- or controlled-release forms.

Even further, the formulations may be delivered in any form, forexample, as a tablet, capsule, pill, spray, solution, paste, cream orany standard way of administering a drug. Formulations may be deliveredin any way that controls the release or availability of the formulation.

Components of the formulations can be given together as a single dose orsequentially in any order as needed or advisable for a particulartrauma, a particular condition or to a particular subject, such as aparticular human.

Components of the formulation can be given with respect to time inrelation to one or more of the onset of a trauma, in anticipation of atrauma, during a trauma, during a period after a trauma and during aperiod of recovery from a trauma. Components of the formulation can beprovided as an initial dose to a subject in accordance with a timingsequence whereby the timing sequence begins with the onset of trauma orbefore the onset of a procedure known to produce trauma in some cases.

In embodiments of the invention utilizing such two or more of compounds,the targets can include any target or targets that activate, enhance orfacilitate processes or pathways that promote health and function ofnerves and nerve cells, and the targets can include any target ortargets that inhibit, attenuate or interfere with processes or pathwaysthat lead to loss of function, injury, damage or death of nerves ornerve cells. Loss of function or injury, damage or cell death can alsoinclude that to neural support cells or neural support tissues.Depending on the specific use and therapeutic context, analogues ormodifications to the specific compounds included in embodiments of thisinvention can be tailored to target specific biological processes orpathways or to facilitate access of compounds to target sites in thecentral, peripheral or enteric nervous systems.

In accordance with yet other aspects of the invention, methods forusing, providing or administering formulations of the invention areprovided. In one preferred embodiment, a method for one or more ofpreventing, reducing the effects of, or reducing the risk of developmentof, neuropathology or neurodegeneration incident to trauma or caused bytrauma is provided. In one advantageous aspect, the method comprises thesteps or actions of A. providing a formulation adapted for theprevention of the development of neuropathology or neurodegeneration,wherein the formulation comprises two biologically active compounds inamounts that are pharmaceutically effective for each compound,respectively, when administered in combination with the otherbiologically active compound, the two compounds respectively comprisinga pharmaceutically effective amount of: i.) at least one biologicallyactive compound from the group comprising anticonvulsants andantiepileptics; and ii.) at least one biologically active compound fromthe group comprising neurosteroids and neuroactive steroids; wherein theformulation is in a form adapted and arranged for administration to amammal in need thereof, such that the development, or the risk ofdevelopment, of neuropathology or neurodegeneration is reduced,lessened, attenuated or prevented, and then, B. administering theformulation to a mammal in need thereof.

In accordance with this and other objects of the invention, numerousembodiments of formulations of the invention for use to treat mammalsare provided. The use of the present formulations will be understood byone of skill in the art to encompass many dosages, circumstances,administrative timing, routes of administration, forms, excipients,controlled release and slow release.

Delivery of compounds of embodiments of the invention, and in accordancewith the methods and procedures described herein, can be effected in anymanner that results in delivery of the compounds of embodiments of theinvention such that positive or negative influence on the target pathwayis accomplished. For example, the formulations can be administered byone or more routes such as, but not limited to oral, buccal, mucosal,parenteral, rectal, sub-cutaneous, transdermal, topical, intravenous,intrathecal, intravaginal, nasal, nasal inhalation, pulmonaryinhalation, iontophoresis through the skin, iontophoresis throughmucosal or buccal membranes, dermal patch, epidural, intracranial,intrapharyngeal, sublingual, intra-articular, intramuscular andsubcutaneous.

In the context of invention embodiments, the term “neural support cell”is any cell that supports or could be considered to support the health,normal function, phenotype, gene expression and survival of nerves andnerve cells, and include, as examples but not exclusively, glial cells,microglia, myelin cells, astroglia, oligodendrocytes, satellite cells,Schwann cells, vascular endothelial cells, gastric epithelial cells,interstitial cells of Cajal, and the like.

In the context of invention embodiments, the term “neural supporttissue” is any tissue that supports or could be considered to supportthe health, normal function, phenotype, normal gene expression orsurvival of nerves, nerve cells or neural support cells, and include, asexamples but not exclusively, the vasculature or microvasculature,particularly the endothelial cells that prevent blood from leaking intonerve tissue and that provide the selective blood-nerve and blood-brainbarrier that allows the passage of certain supportive chemicals intonerve tissue as well as the passage of nerve tissue wastes out of nervetissue, as well as epithelial cells and interstitial cells of Cajal ofthe gut.

Preferably the administered compounds selected will facilitate, promoteor potentiate restorative responses to trauma, and will interfere with,lessen or inhibit degenerative processes. This can occur, for example,by binding to an enzyme, receptor, allosteric site or other step of anendogenous biochemical or biosynthetic pathway to the extent that suchpathway is altered, enabled, allowed or facilitated in its effectivefunctioning, as in the case of restorative processes, or would preventor lessen its effective functioning, as in the case of degenerativeprocesses.

The presently disclosed invention and its embodiments are useful forstrengthening or improving natural processes that help to restore thehealth and function of nerves, nerve cells, neural support cells andneural support tissues when compromised by trauma. Further, thepresently disclosed invention embodiments are also useful for lessening,diminishing or inhibiting natural processes that lead to loss of healthand function of nerves, nerve cells, neural support cells and neuralsupport tissues when caused by trauma.

Other preferred two-component formulations of the invention includethose wherein the anticonvulsant or antiepileptic is at least one formof pregabalin; and B. wherein the neurosteroid or neuroactive steroid isat least one form of progesterone; and wherein the anticonvulsant orantiepileptic is at least one form of gabapentin, and wherein theneurosteroid or neuroactive steroid is at least one form of syntheticprogestin.

Other preferred combinations of the invention include those wherein theanticonvulsant or antiepileptic is at least one form of pregabalin; andthe neurosteroid or neuroactive steroid is at least one form ofsynthetic progestin; as well as that wherein the anticonvulsant orantiepileptic is at least one form of gabapentin; and wherein theneurosteroid or neuroactive steroid is at least one form ofprogesterone.

In yet other aspects of methods for using, providing or administeringformulations of the invention, in another preferred embodiment, thecompound selected from the group comprising anticonvulsants andantiepileptics is at least one form of gabapentin or at least one formof pregabalin; and the compound selected from the group comprisingneurosteroids and neuroactive steroids is at least one form ofprogesterone or synthetic progestin.

In some embodiments of the invention, mammals, and especially humans,are suitable subjects. Of course, other mammals, such as cows, horses,cats, dogs, sheep, pigs and rodents, are suitable subjects for thepresently disclosed invention embodiments.

The presently disclosed technology includes formulations, methods,procedures and combinations thereof directed toward reducing orpreventing the development, or the risk of development, ofneuropathology and neurodegeneration as a result of traumatic injury.Embodiments of the invention address heretofore unmet or unsolvedmedical needs including brain injury, central nervous system ischemia,spinal cord injury, enteric nervous system injury, peripheral nerveinjury and any other injury that can include or affect nerve cells,neural support cells or neural support tissues.

These unmet or unsolved medical needs share the common aspect of thepotential for life-long adverse health conditions or disability. Theyalso share the commonality of the void in current medical interventionsthat attempt to reduce or prevent these adverse health conditions ordisabilities. These conditions also share common mechanisms of thesecondary injury that develops following a primary injury or trauma,common mechanisms that trigger or govern this secondary injury. Theseconditions also share common possible therapeutic targets for inhibitingor promoting the cascades of mechanisms triggered by the primary injury.During the period that these processes continue appropriate medicaltreatment can reduce or prevent the neurological deficits that are thesequelae of these secondary injury processes. Due to the progressivenature of this cascades of events in secondary neuronal injury, theseprocesses are accessible to and available for clinical intervention, andallow the development of new treatments to reduce or prevent thedevelopment of secondary neuronal injury triggered by traumatic events

In another aspect of some embodiments of the invention, the formulationsand methods of the invention include wherein the formulation is adaptedand arranged to be administered with respect to time in relation to thetrauma. Thus, the timing of administration of the formulations of theinvention, or of their respective components, can be adapted to anycircumstance regarding, for example, the timing, the nature, theseverity, the location, the availability and the type of medical oremergency care, or the context of the trauma.

As examples with respect to timing, formulations of the invention areadaptable and arrangeable, or can be adapted and arranged, to beadministered to a mammal in need thereof i) upon the onset of thetrauma, ii.) in anticipation of a possible or potential trauma, hi.)during the trauma, and iv.) during a period of recovery from the trauma.

In a related feature, this timing aspect can be adapted to specificperiods. As one of skill in the art will appreciate, such periods can bedetermined with respect to any factor regarding the health or conditionof the trauma victim. Such factors or conditions include, as examples,the nature, type, severity, location, the sex or gender, the age, anycontinuing or predisposing health or medical condition, the type andextent of other injuries sustained as a result of the trauma, the natureof a known or potential trauma that is anticipated on the basis of knownor probable risk, the resourcefulness of other personnel in theimmediate context or area, the proximity of critical care or emergencymedical or paramedical personnel, the complement of critical care oremergency facilities immediately available at the scene of the trauma,the availability of full emergency or healthcare facilities, and theproximity to full emergency or healthcare facilities.

Examples of such periods include, inter glia, wherein the formulation isadapted and arranged to be first administered within two hours after thetrauma, wherein the formulation is adapted and arranged to be firstadministered as a single dosage unit within 24 hours after the onset ofthe trauma, wherein the formulation is adapted and arranged to be firstadministered preventively or prophylactically within 6 hours before theexpected onset of the trauma as a single dosage unit, and wherein theformulation is adapted and arranged to be administered additionally oneor a plurality of times after the formulation is first administered.

In accordance with this and other objects of the invention, numerousembodiments of formulations of the invention for use to treat mammalsare provided. The use of the present formulations will be understood byone of skill in the art to encompass many dosages, circumstances,administrative timing, route of administration, forms of administration,excipients, controlled release.

As such mechanisms are triggered immediately by trauma, while otherstemporally downstream or spatially distant in the cascades ofbiochemical and metabolic pathways are engaged at different times andsites following trauma, it is necessary to administer the componentscomprising the formulation during the hours, days and in some cases, theweeks and months following trauma, with immediate or earliest possibleinitiation of treatment of paramount importance for the preventivemeasures to arrest the degenerative cascades and to promote therestorative cascades, as well as continuation of practice according toneed.

Quite apart from the mechanisms involved in causing secondary injury isthe issue of initiation of treatment. In a recent study on post-traumahealth care for patients suffering severe traumatic brain injury, themedian time to arrival of ambulance staff at the scene of a vehicleaccident was 9 minutes (range 2-35 min), while the median time toarrival at a trauma centre was 6 hours, suggesting that to achieve theearliest intervention to reduce or prevent secondary neuropathologyinjury, the intervention should be administered by trained personnel atthe site of accident or trauma. While the authors state that the effectof prolonged pre-hospital time on outcome from brain injury is unknown,they conclude that in their study patients did not seem to be harmed bya prolonged pre-hospital time; it is noteworthy in this respect thatthey did not include a long-term follow-up study in their report tosupport this statement. They did not compare pre-hospital time tofunctional or disability outcomes months later to substantiate theirconclusion. The conclusion from this study is markedly different fromthe clinical consensus that early treatment reduces mortality afterbrain injury and the focus of the presently disclosed technology and itsembodiments is therefore on a polypharmacy approach to immediate,sequential and timed methods and procedures, administering a formulationof neurotrophic and neuroprotective pharmaceuticals to reduce or preventthe development, or the risk of development, of neuropathology andneurodegeneration that result from trauma

Evidence indicates that once the secondary damage due to trauma hasbecome entrenched, little can be done therapeutically other thanattempts to manage symptoms.

A different rationale or approach to standard practice is thus justifiedand is critically needed, which is to intervene immediately in theprocesses governing, producing or developing secondary damage ratherthan only seeking later rehabilitation treatment for establishedsymptoms. That is, in view of the evidence that current medicalintervention fails to treat adverse health outcomes or disabilityresulting from brain injury an option of choice becomes developing amedical intervention to prevent the processes that lead to these adversehealth outcomes and to promote natural restorative processes.

Trauma to the nervous system, or neurotrauma, often referred to as“acquired nerve injury,” is a catastrophic injury that imposes a numberof negative outcomes that usually inflict one or more adverse healthconditions or disabilities on its victims. These adverse healthconditions and disabilities frequently place both short-term andlong-term burdens on individuals, families, communities, the workplace,the health care system and economies in general. Few or no currentpractices are directed at attempts to lessen, prevent or ameliorate theeffects of trauma on secondary injury. Until the presently disclosedformulations, methods and procedures, no satisfactory methods orpharmaceutical treatments have been successful at preventing or reducingthe secondary injury, or neuropathology, associated with trauma and itssequelae.

The pathological changes, and the mechanisms or processes of secondaryinjury are shared by brain injury, central nervous system ischemia,spinal cord injury, peripheral nervous system injury and enteric nervoussystem injury. The many embodiments of the presently disclosed inventionare directed at preventing or reducing the development of the sequelaeof negative effects and symptoms that incidence studies indicate followany of these types of trauma, and that can continue for months or years,or even permanently.

Parenthetically, in the context of the presently disclosed inventionembodiments, prevention does not imply avoidance. Prevention in thecontext of avoidance would be, as examples, avoiding falls, wearing bodyarmor, wearing seat belts, wearing helmets while bicycling, and thelike. Prevention in the context of the presently disclosed inventionembodiments is administration of a pharmaceutically effective dose of aformulation of two or more chemical entities, following methods,procedures and practices, with the objective to reduce or preventsecondary injury by inhibiting or interfering with the naturaldegenerative processes triggered by trauma and to promote recovery andrepair by enhancing or promoting the natural restorative processestriggered by this same trauma.

As a person having ordinary skill in the art will understand,pharmaceutical compositions, methods, procedures and means ofadministration of the presently disclosed invention are useful fortreating or preventing any type of neuropathology such as, but notlimited to, those characterized as brain injury, central nervous systemischemia, spinal cord injury, enteric nervous system injury andperipheral nerve injury as described herein. Also included among themany conditions that can be treated or prevented by the pharmaceuticalcompositions, methods and procedures of the presently disclosedinvention are disturbances of any etiology so long as involvement of anyprocess or pathway is involved that can be modified or altered by ananticonvulsant/antiepileptic or neurosteroid/neuroactive steroid, or anyanalog, derivative or related compound.

The presently disclosed invention embodiments are based at least in somepart upon Applicant's speculation that many of the negative outcomes anddisabilities of trauma-induced neuropathology and neurodegeneration canbe reduced in severity, or prevented altogether, by appropriate earlyintervention with one or more of the present methods, procedures andpharmaceutical formulations, especially when continued for a medicallybeneficial period of time. There are currently rehabilitation practicesand interventions to treat or manage the disabilities that have resultedfrom a trauma to nerve cells and neural support cells once they havebeen established. Rehabilitation treatment for victims of traumatypically focuses on symptoms that are already established. Suchtreatment is usually initiated months or even years after a traumaticevent, and is usually the result of patient requests for relief ofdebilitating symptoms that have become permanent. Applicant posits thatin these cases long-term symptoms are preventable or can be reduced, ifthe appropriate medical intervention and procedure is applied and ifthis intervention is applied at the time when the processes that wouldculminate in disability are underway. However, immediate or earlyapproaches targeted at the development phase of these outcomes areunknown, few or ineffective.

Illustrative of the failings of the current “conventional” treatmentsare those provided at the time of a traumatic event, wherebyconventional medical attention focuses on the treatment of immediatesymptoms such as bleeding and maintaining adequate respiration, or toavoid or prevent infection, and do not even recognize the advantages ofthe present invention. Disadvantageously, currently conventional medicalpractice does not recognize the advantages of treatment to promote thecascades of restorative processes, as well as to prevent or reduce thecascades of degenerative processes, which result from trauma and thatgovern the prolonged or permanent adverse health conditions anddisability that can and often do result from trauma. It is this lattertreatment modality, i.e., effecting treatment to prevent or reducedamage from the secondary sequelae, that the presently disclosedtechnology is directed.

In the context of the presently disclosed invention embodimentsprevention does not imply avoidance. Prevention in the context ofavoidance would be, as examples, avoiding falls, wearing body armor,wearing seat belts, wearing helmets while bicycling, and the like.Prevention in the context of the presently disclosed inventionembodiments is administration of a pharmaceutically effective dose of aformulation of two or more chemical entities, following methods,procedures and practices with the objective to reduce or preventsecondary injury by inhibiting or interfering with the naturaldegenerative processes triggered by trauma and to promote recovery andrepair by enhancing or promoting the natural restorative processestriggered by this same trauma. Prevention in the context of thepresently disclosed invention embodiments is inhibition ofneurodegeneration processes and promotion of restorative processes.

There is an additional aspect, or advantage, of the present invention.For example, as trauma to the brain is known to increase the risk of thelater development of some degenerative disorders, the presentlydisclosed technology is also directed at reducing or preventing the riskof longer-term neurodegeneration. Head trauma is a medically known riskfactor for Parkinson's disease; stroke is a medically known risk factorfor Alzheimer's disease. Further, slow degenerative disease is suspectedin many athletes who have undergone multiple head traumas, such as infootball, hockey and boxing; this manifests as mood swings, depressionand forgetfulness that develop in athletes years after retirement from asport, and also include Parkinson's disease, Alzheimer's disease,amyotrophic lateral sclerosis, multiple sclerosis, subacuteposttraumatic ascending myelopathy and the like. Applicant posits thatthese manifestations of head trauma can be prevented or reduced byapplication or practice of the presently disclosed technology. Somevictims of head trauma or repeated concussions or minor head injuriesare driven to suicide. Applicant posits that at least some of thesesuicides may be prevented by application or practice of the presentlydisclosed technology, according to the methods and practices describedherein.

Another striking example of progressive or developing neurodegenerationincludes posttraumatic stress disorder that develops in soldiers weeksor even months after serving active duty. In 2012 more US soldiers diedfrom suicide than were killed in combat in Afghanistan: 349 died fromsuicide, 295 died in combat. Applicant posits as well that at least somesuicides in soldiers may be prevented by application or practice of thepresently disclosed technology, according to the methods and practicesdescribed herein.

Objects and Description of the Invention

It is therefore an object of the invention to provide formulationsadapted and arranged for accomplishing one or more of preventing,ameliorating, lessening or eliminating the damages incident to manykinds and types of trauma to mammals, and especially to human beings.

It is another object of the invention to provide methods and means foradministering formulations of the invention to accomplish these samegoals and effects.

It is also an object of the invention to provide methods and meanscombined with formulations to be administered with respect to the timeof the trauma, including beforehand, during, immediately afterward, andin a sustained manner for hours, days, weeks or months thereafter.

In accordance with these and other objects, formulations of theinvention are adapted and provided for the prevention of the developmentof neuropathology and neurodegeneration, and for the amelioration of theeffects caused by trauma to a subject, the formulation comprising twobiologically active compounds. Preferably, the two biologically activecompounds are provided in amounts that are pharmaceutically effectivefor each compound, respectively, when administered in combination withthe other biologically active compound. In some preferred embodiments ofthe invention, the two compounds comprise a pharmaceutically effectiveamount of A) at least one biologically active compound selected from thegroup comprising anticonvulsant and antiepileptics, wherein theanticonvulsant/antiepileptic is at least one form of pregabalin; B) atleast one biologically active compound from the group comprisingneurosteroids and neuroactive steroids, wherein theneurosteroid/neuroactive steroidal agent is at least one form ofprogesterone or synthetic progestin.

In accordance with these and other objects, formulations of theinvention are adapted and provided for the prevention of the developmentof neuropathology and neurodegeneration, and for the amelioration of theeffects caused by trauma to a subject, the formulation comprising twobiologically active compounds. Preferably, the two biologically activecompounds are provided in amounts that are pharmaceutically effectivefor each compound, respectively, when administered in combination withthe other biologically active compound. In some preferred embodiments ofthe invention, the two compounds comprise a pharmaceutically effectiveamount of A) at least one biologically active compound selected from thegroup comprising anticonvulsant and antiepileptics, wherein theanticonvulsant/antiepileptic is at least one form of gabapentin; B) atleast one biologically active compound from the group comprisingneurosteroids and neuroactive steroids, wherein theneurosteroid/neuroactive steroidal agent is at least one form ofprogesterone or synthetic progestin.

In accordance with these and other objects, formulations of theinvention are adapted and provided for the prevention of the developmentof neuropathology and neurodegeneration, and for the amelioration of theeffects caused by trauma to a subject, the formulation comprising two orthree biologically active compounds. Preferably, the two or threebiologically active compounds are provided in amounts that arepharmaceutically effective for each compound, respectively, whenadministered in combination with the other biologically activecompounds. In some preferred embodiments of the invention, the threecompounds comprise a pharmaceutically effective amount of A) at leastone biologically active compound selected from the group comprisinganticonvulsant and antiepileptics, wherein theanticonvulsant/antiepileptic is at least one form of one or more ofpregabalin; B) at least one biologically active compound from the groupcomprising neurosteroids and neuroactive steroids, wherein theneurosteroid/neuroactive steroidal agent is at least one form of one ormore selected from the group comprising progesterone or syntheticprogestin; C) at least one biologically active compound from the groupcomprising lithium-containing and lithium-related compounds, wherein thelithium-containing/lithium-related compound is at least one form of oneor more of lithium carbonate.

In accordance with these and other objects, formulations of theinvention are adapted and provided for the prevention of the developmentof neuropathology and neurodegeneration, and for the amelioration of theeffects caused by trauma to a subject, the formulation comprising two orthree biologically active compounds. Preferably, the two or threebiologically active compounds are provided in amounts that arepharmaceutically effective for each compound, respectively, whenadministered in combination with the other biologically activecompounds. In some preferred embodiments of the invention, the threecompounds comprise a pharmaceutically effective amount of A) at leastone biologically active compound selected from the group comprisinganticonvulsant and antiepileptics, wherein theanticonvulsant/antiepileptic is at least one form of one or more ofgabapentin; B) at least one biologically active compound from the groupcomprising neurosteroids and neuroactive steroids, wherein theneurosteroid/neuroactive steroidal agent is at least one form of one ormore selected from the group comprising progesterone or syntheticprogestin; C) at least one biologically active compound from the groupcomprising lithium-containing and lithium-related compounds, wherein thelithium-containing/lithium-related compound is at least one form of oneor more of lithium carbonate.

Advantageously, the formulations of the invention are provided in a formand a dosage with respect to each of the formulations' components orcompounds such that a formulation of the invention is adapted andarranged for administration to a mammal in need thereof, such as ahuman, so that the development, or the risk of development, ofneuropathology and neurodegeneration is reduced, lessened, attenuated orprevented. The formulations and methods of the invention areparticularly useful in the treatment of human beings.

Particular Embodiments

In accordance with these and other objects, the present inventionprovides many embodiments of its formulations, methods, procedures andmeans for treating any neuropathological condition that is the resultof, or incident to, at least partially, trauma of any kind. The presentformulations, methods and procedures advantageously affect cellular andtissue function, such as endogenous processes or biosynthetic andmetabolic process pathways that govern, regulate or influence the healthor function of nerves or nerve cells, or cells upon which nerves ornerve cells depend to maintain health and function. As an aspect of thepresently disclosed technology, the formulations are preferably in formsand at dosages with respect to each of the respective components suchthat any of the formulations are adapted and arranged for administrationto a mammal in need thereof, such that the development, or the risk ofdevelopment, of neuropathology and neurodegeneration is reduced,lessened, attenuated or prevented.

In general, the presently disclosed technology comprises formulationsadapted for the prevention of the development of neuropathology andneurodegeneration, or for the amelioration of the effects caused bytrauma to a subject, the formulation comprising biologically activecompounds from three groups of compounds in amounts that arepharmaceutically effective for each compound, respectively, whenadministered in combination with the other two biologically activecompounds.

In accordance with a key aspect of three-component embodiments of theinvention, the formulation comprises, or consists essentially of, apharmaceutically effective amount of at least one biologically activecompound from three groups of compounds. These three groups are A)anticonvulsants and antiepileptics, B) neurosteroids and neuroactivesteroids, and C) lithium-containing and lithium-related compounds.

A formulation of the invention comprises, or consists essentially of, apharmaceutically effective amount of at least one compound from thegroup consisting of anticonvulsants and antiepileptics, apharmaceutically effective amount of at least one biologically activecompound from the group consisting of neurosteroids and neuroactivesteroids, and a pharmaceutically effective amount of at least onebiologically active compound from the group consisting oflithium-containing and lithium-related compounds.

In accordance with other aspects of the invention, formulations of theinvention are adapted for delivery to a mammal in need thereof withwhatever delivery component, components or systems which are necessaryto effect such delivery. Such components or systems include things suchas excipients, buffers, penetration enhancers, stabilizers, absorptionenhancers binders, coatings, transport enhancers, chelators, carriers,clearance modifiers, emulsifying agents, antioxidants, preservatives,sugars, salts, cellulose, dyes, flavoring agents and any other inactiveingredients that are considered generally recognized as safe.

The present invention is thus adapted and arranged to facilitate thetreatment of cells, tissues, organs and combinations thereof that areaffected or caused by trauma.

Formulations of the invention can thus be adapted and arranged to bedirected toward any target or targets that activate, enhance orfacilitate processes or pathways that promote health and function ofnerves and nerve cells or that inhibit, attenuate or interfere withprocesses or pathways that lead to loss of function, injury, damage ordeath of nerves or nerve cells. Loss of function or injury, damage orcell death can also include the effects of trauma to nerve cells, neuralsupport cells or neural support tissues.

In general, the presently disclosed technology comprises formulations,methods and procedures for administering to a mammal in need thereof, atherapeutically effective amount of three biologically active compoundswhich can be targeted to enhance or facilitate processes or pathwaysthat promote health and function of nerves and nerve cells or thatinhibit, attenuate or interfere with processes or pathways that lead toloss of function, injury, damage or death of nerves or nerve cells.Targeted functions can also be those that include loss of function,injury, and damage or cell death including that to nerve cells, neuralsupport cells or neural support tissues.

In general, the presently disclosed technology comprises a two-componentformulation adapted for the prevention of the development ofneuropathology or neurodegeneration, or for the amelioration of theeffects caused by trauma to a subject, the formulation comprising twobiologically active compounds in amounts that are pharmaceuticallyeffective for each compound, respectively, when administered incombination with the other biologically active compound, the formulationcomprising at least one biologically active compound from the groupcomprising anticonvulsants and antiepileptics, wherein theanticonvulsant or antiepileptic is at least one form of pregabalin andat least one biologically active compound from the group comprisingneurosteroids and neuroactive steroids, wherein the neurosteroid orneuroactive steroid is at least one form of progesterone or syntheticprogestin.

In general, the presently disclosed technology comprises a two-componentformulation adapted for the prevention of the development ofneuropathology or neurodegeneration, or for the amelioration of theeffects caused by trauma to a subject, the formulation comprising twobiologically active compounds in amounts that are pharmaceuticallyeffective for each compound, respectively, when administered incombination with the other biologically active compound, the formulationcomprising at least one biologically active compound from the groupcomprising anticonvulsants and antiepileptics, wherein theanticonvulsant or antiepileptic is at least one form of gabapentin andat least one biologically active compound from the group comprisingneurosteroids and neuroactive steroids, wherein the neurosteroid orneuroactive steroid is at least one form of progesterone or syntheticprogestin.

In general, the presently disclosed technology comprises athree-component formulation adapted for the prevention of thedevelopment of neuropathology and neurodegeneration, or for theamelioration of the effects caused by trauma to a subject, theformulation comprising three biologically active compounds in amountsthat are pharmaceutically effective for each compound, respectively,when administered in combination with the other two biologically activecompounds, the formulation comprising at least one biologically activecompound from the group comprising anticonvulsants and antiepileptics,wherein the anticonvulsant or antiepileptic is at least one form ofpregabalin, at least one biologically active compound from the groupcomprising neurosteroids and neuroactive steroids, wherein theneurosteroid or neuroactive steroid is at least one form of progesteroneor synthetic progestin, and at least one biologically active compoundfrom the group comprising lithium-containing and lithium-relatedcompounds wherein the lithium-containing or lithium-related compound isat least one form of lithium carbonate.

In general, the presently disclosed technology comprises athree-component formulation adapted for the prevention of thedevelopment of neuropathology and neurodegeneration, or for theamelioration of the effects caused by trauma to a subject, theformulation comprising three biologically active compounds in amountsthat are pharmaceutically effective for each compound, respectively,when administered in combination with the other two biologically activecompounds, the formulation comprising at least one biologically activecompound from the group comprising anticonvulsants and antiepileptics,wherein the anticonvulsant or antiepileptic is at least one form ofgabapentin, at least one biologically active compound from the groupcomprising neurosteroids and neuroactive steroids, wherein theneurosteroid or neuroactive steroid is at least one form of progesteroneor synthetic progestin, and at least one biologically active compoundfrom the group comprising lithium-containing and lithium-relatedcompounds wherein the lithium-containing or lithium-related compound isat least one form of lithium carbonate.

Many dosages, dosage ranges and combinations of the essential twocomponents of the present formulations are within the scope and spiritof the invention. As one of many preferred embodiments, in a formulationof the invention, the pregabalin is provided in a dosage range of fromabout 5.0 mg to about 9,600 mg and the progesterone or syntheticprogestin is provided in a dosage range of from about 0.05 mg to about1,200 mg.

Many dosages, dosage ranges and combinations of the essential twocomponents of the present formulations are within the scope and spiritof the invention. As one of many preferred embodiments, in a formulationof the invention, the pregabalin is provided in a dosage range of fromabout 0.5 mg to about 2,400 mg and the progesterone or syntheticprogestin is provided in a dosage range of from about 0.05 mg to about1,200 mg.

Many dosages, dosage ranges and combinations of the essential twocomponents of the present formulations are within the scope and spiritof the invention. As one of many preferred embodiments, in a formulationof the invention, the gabapentin is provided in a dosage range of fromabout 5.0 mg to about 9,600 mg and the progesterone or syntheticprogestin is provided in a dosage range of from about 0.05 mg to about1,200 mg.

Alternatively, in the formulation the pregabalin is provided in a dosagerange of from about 15 mg to about 1,200 mg and the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg. As a further alternative, in the formulation thepregabalin is provided in a dosage range of from about 25 mg to about600 mg and the progesterone or synthetic progestin is provided in adosage range of from about 40 mg to about 450 mg.

Alternatively, in the formulation the gabapentin is provided in a dosagerange of from about 50 mg to about 4,800 mg and the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg. As a further alternative, in the formulation thegabapentin is provided in a dosage range of from about 100 mg to about2,400 mg and the progesterone or synthetic progestin is provided in adosage range of from about 50 mg to about 450 mg.

In yet another preferred embodiment, some formulations of the inventioninclude wherein the pregabalin is provided in a dosage range of fromabout 50 mg to about 150 mg and the progesterone or synthetic progestinis provided in a dosage range of from about 100 mg to about 300 mg.

In yet another preferred embodiment, some formulations of the inventioninclude wherein the gabapentin is provided in a dosage range of fromabout 200 mg to about 600 mg and the progesterone or synthetic progestinis provided in a dosage range of from about 100 mg to about 300 mg.

The present invention also includes methods, procedures and means whichare adapted and arranged to utilize two-component formulations for oneor more of preventing, reducing the effects of, or reducing the risk ofdevelopment of, neuropathology and neurodegeneration incident to trauma.In one significant aspect, a preferred method or procedure of theinvention comprises the steps or actions of A) providing a formulationadapted for the prevention of the development of neuropathology, whereinthe formulation comprises two biologically active compounds in amountsthat are pharmaceutically effective for each compound, respectively,when administered in combination with the other biologically activecompound, the two compounds respectively comprising i) apharmaceutically effective amount of at least one biologically activecompound from the group comprising anticonvulsants and antiepilepticdrugs, and ii) a pharmaceutically effective amount of at least onebiologically active compound from the group comprising neurosteroids andneuroactive steroids; and then B) administering the formulation to amammal in need thereof.

In a yet more specific embodiment, another preferred method or procedureof the invention comprises the steps or actions of A) providing aformulation adapted for the prevention of the development ofneuropathology, wherein the formulation comprises two biologicallyactive compounds in amounts that are pharmaceutically effective for eachcompound, respectively, when administered in combination with the otherbiologically active compound, the two compounds respectively comprisingi) a pharmaceutically effective amount of at least one biologicallyactive compound from the group comprising anticonvulsants andantiepileptic drugs wherein the anticonvulsant/antiepileptic drug ispregabalin and ii) at least one biologically active compound from thegroup comprising neurosteroids and neuroactive steroids wherein theneurosteroid or neuroactive steroid is progesterone; and then B)administering the formulation to a mammal in need thereof.

In a yet more specific embodiment, another preferred method or procedureof the invention comprises the steps or actions of A) providing aformulation adapted for the prevention of the development ofneuropathology, wherein the formulation comprises two biologicallyactive compounds in amounts that are pharmaceutically effective for eachcompound, respectively, when administered in combination with the otherbiologically active compound, the two compounds respectively comprisingi) a pharmaceutically effective amount of at least one biologicallyactive compound from the group comprising anticonvulsants andantiepileptic drugs wherein the anticonvulsant/antiepileptic drug isgabapentin and ii) at least one biologically active compound from thegroup comprising neurosteroids and neuroactive steroids wherein theneurosteroid or neuroactive steroid is progesterone; and then B)administering the formulation to a mammal in need thereof.

In the presently disclosed technology, administration in accordance withthe present methods and procedures includes that for delivering atwo-component formulation wherein the at least oneanticonvulsant/antiepileptic is pregabalin and the at least oneneurosteroid/neuroactive steroid is progesterone or synthetic progestin.

In the presently disclosed technology, administration in accordance withthe present methods and procedures includes that for delivering atwo-component formulation wherein the at least oneanticonvulsant/antiepileptic is gabapentin and the at least oneneurosteroid/neuroactive steroid is progesterone or synthetic progestin.

In the context of a preferred method or procedure of the presentinvention utilized to effect the administration of one of thetwo-component formulations, the pregabalin is provided in a dosage rangeof from about 0.5 mg to about 2,400 mg and the progesterone or syntheticprogestin is provided in a dosage range of from about 0.05 mg to about1,200 mg.

In the context of a preferred method or procedure of the presentinvention utilized to effect the administration of one of thetwo-component formulations, the gabapentin is provided in a dosage rangeof from about 5.0 mg to about 9,600 mg and the progesterone or syntheticprogestin is provided in a dosage range of from about 0.05 mg to about1,200 mg.

In a similar context for a method or procedure for administration of aformulation of the invention, the pregabalin is provided in a dosagerange of from about 15 mg to about 1,200 mg and the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg. Even further, for administration of the formulation, thepregabalin is provided in a dosage range of from about 25 mg to about600 mg and the progesterone or synthetic progestin is provided in adosage range of from about 50 mg to about 450 mg.

In a similar context for a method or procedure for administration of aformulation of the invention, the gabapentin is provided in a dosagerange of from about 50 mg to about 4,800 mg and the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg. Even further, for administration of the formulation, thegabapentin is provided in a dosage range of from about 100 mg to about2,400 mg and the progesterone or synthetic progestin is provided in adosage range of from about 50 mg to about 450 mg.

Yet even further, for a method or procedure for administration of one ofthe present two-component formulations, the pregabalin is provided in adosage range of from about 50 mg to about 150 mg and the progesterone orsynthetic progestin is provided in a dosage range of from about 100 mgto about 300 mg.

Yet even further, for a method or procedure for administration of one ofthe present two-component formulations, the gabapentin is provided in adosage range of from about 200 mg to about 600 mg and the progesteroneor synthetic progestin is provided in a dosage range of from about 100mg to about 300 mg.

Many dosages, dosage ranges and combinations of the essential threecomponents of the present formulations are within the scope and spiritof the invention. As one of many preferred embodiments, in a formulationof the invention, the pregabalin is provided in a dosage range of fromabout 0.5 mg to about 2,400 mg, the progesterone or synthetic progestinis provided in a dosage range of from about 0.05 mg to about 1,200 mg,and the lithium carbonate is provided in a dosage range of from about0.5 mg to about 3,600 mg.

Many dosages, dosage ranges and combinations of the essential threecomponents of the present formulations are within the scope and spiritof the invention. As one of many preferred embodiments, in a formulationof the invention, the gabapentin is provided in a dosage range of fromabout 5.0 mg to about 9,600 mg, the progesterone or synthetic progestinis provided in a dosage range of from about 0.05 mg to about 1,200 mg,and the lithium carbonate is provided in a dosage range of from about0.5 mg to about 3,600 mg.

Alternatively, in the formulation the pregabalin is provided in a dosagerange of from about 15 mg to about 1,200 mg, the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg, and the lithium carbonate is provided in a dosage range offrom about 30 mg to about 1,800 mg. As a further alternative, in theformulation the pregabalin is provided in a dosage range of from about25 mg to about 600 mg, the progesterone or synthetic progestin isprovided in a dosage range of from about 50 mg to about 450 mg, and thelithium carbonate is provided in a dosage range of from about 100 mg toabout 900 mg.

Alternatively, in the formulation the gabapentin is provided in a dosagerange of from about 50 mg to about 4,800 mg, the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg, and the lithium carbonate is provided in a dosage range offrom about 30 mg to about 1,800 mg. As a further alternative, in theformulation the gabapentin is provided in a dosage range of from about100 mg to about 2,400 mg, the progesterone or synthetic progestin isprovided in a dosage range of from about 50 mg to about 450 mg, and thelithium carbonate is provided in a dosage range of from about 100 mg toabout 900 mg.

In yet another preferred embodiment, some formulations of the inventioninclude wherein the pregabalin is provided in a dosage range of fromabout 50 mg to about 150 mg, the progesterone or synthetic progestin isprovided in a dosage range of from about 100 mg to about 300 mg, and thelithium carbonate is provided in a dosage range of from about 200 mg toabout 600 mg.

In yet another preferred embodiment, some formulations of the inventioninclude wherein the gabapentin is provided in a dosage range of fromabout 200 mg to about 600 mg, the progesterone or synthetic progestin isprovided in a dosage range of from about 100 mg to about 300 mg, and thelithium carbonate is provided in a dosage range of from about 200 mg toabout 600 mg.

The present invention also includes methods, procedures and means whichare adapted and arranged to utilize three-component formulations for oneor more of preventing, reducing the effects of, or reducing the risk ofdevelopment of, neuropathology and neurodegeneration incident to trauma.In one significant aspect, a preferred method or procedure of theinvention comprises the steps or actions of A) providing a formulationadapted for the prevention of the development of neuropathology andneurodegeneration, wherein the formulation comprises three biologicallyactive compounds in amounts that are pharmaceutically effective for eachcompound, respectively, when administered in combination with the othertwo biologically active compounds, the three compounds respectivelycomprising i) a pharmaceutically effective amount of at least onebiologically active compound from the group comprising anticonvulsantsand antiepileptic drugs, ii) a pharmaceutically effective amount of atleast one biologically active compound from the group comprisingneurosteroids and neuroactive steroids, and iii) at least onebiologically active compound from the group comprisinglithium-containing and lithium-related drugs; and then B) administeringthe formulation to a mammal in need thereof.

In a more specific embodiment, another preferred method or procedure ofthe invention comprises the steps or actions of A) providing aformulation adapted for the prevention of the development ofneuropathology and neurodegeneration, wherein the formulation comprisesthree biologically active compounds in amounts that are pharmaceuticallyeffective for each compound, respectively, when administered incombination with the other two biologically active compounds, the threecompounds respectively comprising i) a pharmaceutically effective amountof at least one biologically active compound from the group comprisinganticonvulsants and antiepileptic drugs wherein theanticonvulsant/antiepileptic drug is pregabalin, ii) at least onebiologically active compound from the group comprising neurosteroids andneuroactive steroids wherein the neurosteroid or neuroactive steroid isprogesterone, and iii) at least one biologically active compound fromthe group comprising lithium-containing and lithium-related drugswherein the lithium-containing or lithium-related drug is lithiumcarbonate; and then B) administering the formulation to a mammal in needthereof.

In a more specific embodiment, another preferred method or procedure ofthe invention comprises the steps or actions of A) providing aformulation adapted for the prevention of the development ofneuropathology and neurodegeneration, wherein the formulation comprisesthree biologically active compounds in amounts that are pharmaceuticallyeffective for each compound, respectively, when administered incombination with the other two biologically active compounds, the threecompounds respectively comprising i) a pharmaceutically effective amountof at least one biologically active compound from the group comprisinganticonvulsants and antiepileptic drugs wherein theanticonvulsant/antiepileptic drug is gabapentin, ii) at least onebiologically active compound from the group comprising neurosteroids andneuroactive steroids wherein the neurosteroid or neuroactive steroid isprogesterone, and iii) at least one biologically active compound fromthe group comprising lithium-containing and lithium-related drugswherein the lithium-containing or lithium-related drug is lithiumcarbonate; and then B) administering the formulation to a mammal in needthereof.

In the presently disclosed technology, administration in accordance withthe present methods and procedures includes that for delivering athree-component formulation wherein the at least oneanticonvulsant/antiepileptic is pregabalin, the at least oneneurosteroid/neuroactive steroid is progesterone or synthetic progestin,and the at least one biologically lithium-containing/lithium-relatedcompound is lithium carbonate.

In the presently disclosed technology, administration in accordance withthe present methods and procedures includes that for delivering athree-component formulation wherein the at least oneanticonvulsant/antiepileptic is gabapentin, the at least oneneurosteroid/neuroactive steroid is progesterone or synthetic progestin,and the at least one biologically lithium-containing/lithium-relatedcompound is lithium carbonate.

In the context of a preferred method or procedure of the presentinvention utilized to effect the administration of one of thethree-component formulations, the pregabalin is provided in a dosagerange of from about 0.5 mg to about 2,400 mg, the progesterone orsynthetic progestin is provided in a dosage range of from about 0.05 mgto about 1,200 mg, and the lithium carbonate is provided in a dosagerange of from about 0.5 to about 3,600 mg.

In the context of a preferred method or procedure of the presentinvention utilized to effect the administration of one of thethree-component formulations, the gabapentin is provided in a dosagerange of from about 5.0 mg to about 9,600 mg, the progesterone orsynthetic progestin is provided in a dosage range of from about 0.05 mgto about 1,200 mg, and the lithium carbonate is provided in a dosagerange of from about 0.5 to about 3,600 mg.

In a similar context for a method or procedure for administration of aformulation of the invention, the pregabalin is provided in a dosagerange of from about 15 mg to about 1,200 mg, the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg, and the lithium carbonate is provided in a dosage range offrom about 30 mg to about 1,800 mg. Even further, for administration ofthe formulation, the pregabalin is provided in a dosage range of fromabout 25 mg to about 600 mg, the progesterone or synthetic progestin isprovided in a dosage range of from about 50 mg to about 450 mg, and thelithium carbonate is provided in a dosage range of from about 100 mg toabout 900 mg.

In a similar context for a method or procedure for administration of aformulation of the invention, the gabapentin is provided in a dosagerange of from about 50 mg to about 4,800 mg, the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg, and the lithium carbonate is provided in a dosage range offrom about 30 mg to about 1,800 mg. Even further, for administration ofthe formulation, the gabapentin is provided in a dosage range of fromabout 100 mg to about 2,400 mg, the progesterone or synthetic progestinis provided in a dosage range of from about 50 mg to about 450 mg, andthe lithium carbonate is provided in a dosage range of from about 100 mgto about 900 mg.

Yet even further, for a method or procedure for administration of one ofthe present three-component formulations, the pregabalin is provided ina dosage range of from about 50 mg to about 150 mg, the progesterone orsynthetic progestin is provided in a dosage range of from about 100 mgto about 300 mg, and the lithium carbonate is provided in a dosage rangeof from about 200 mg to about 600 mg.

Yet even further, for a method or procedure for administration of one ofthe present three-component formulations, the gabapentin is provided ina dosage range of from about 200 mg to about 600 mg, the progesterone orsynthetic progestin is provided in a dosage range of from about 100 mgto about 300 mg, and the lithium carbonate is provided in a dosage rangeof from about 200 mg to about 600 mg.

In general, the present invention comprises four-component formulations,methods and procedures adapted for the prevention of the development ofneuropathology and neurodegeneration, or for the amelioration of theeffects caused by trauma to a subject, the formulation comprisingbiologically active compounds from four groups in amounts that arepharmaceutically effective for each compound, respectively, whenadministered in combination with the other three biologically activecompounds.

In accordance with a key aspect of a four-component embodiment of theinvention, the formulation to be delivered by a method or procedure ofthe present technology comprises, or consists essentially of, apharmaceutically effective amount of at least one biologically activecompound selected from four groups of compounds. These four groups areA) anti-convulsants and antiepileptics, B) neurosteroids and neuroactivesteroids, C) lithium-containing and lithium-related compounds, and D) apharmaceutically effective amount of at least one biologically activecompound from the group comprising substance P receptor (NK-1 receptor)antagonists. Thus, a formulation of the invention comprises, or consistsessentially of, a pharmaceutically effective amount of at least onecompound from the group consisting of anticonvulsants andantiepileptics, a pharmaceutically effective amount of at least onebiologically active compound from the group consisting of neurosteroidsand neuroactive steroids, a pharmaceutically effective amount of atleast one biologically active compound from the group consisting oflithium-containing and lithium-related compounds, and a pharmaceuticallyeffective amount of at least one biologically active compound from thegroup comprising substance P receptor (NK-1 receptor) antagonists.

In accordance with other aspects of the invention, formulations of theinvention are adapted for delivery to a mammal in need thereof by way ofmethods and procedures of the invention with whatever deliverycomponent, components or systems that are necessary to effect suchdelivery. Such components or systems include compounds or things such asexcipients, buffers, penetration enhancers, stabilizers, absorptionenhancers binders, coatings, transport enhancers, chelators, carriers,clearance modifiers, emulsifying agents, antioxidants, preservatives,sugars, salts, cellulose, dyes, flavoring agents and any other inactiveingredients that are considered generally recognized as safe. Thepresent invention is thus adapted and arranged to facilitate thetreatment of cells, tissues, organs and combinations thereof which areaffected by neurotrauma. Formulations of the invention can thus beadapted and arranged to be directed toward any cellular, tissue orsystem target or targets that activate, enhance or facilitate processesor pathways that promote health and function of nerves and nerve cellsor that inhibit, attenuate or interfere with processes or pathways thatlead to loss of function, injury, damage or death of nerves or nervecells. Loss of function or injury, damage or cell death can also includethe effects of trauma to neural support cells or neural support tissues.

In its many preferred four-component embodiments, the present inventioncomprises formulations adapted for the prevention of the development ofneuropathology and neurodegeneration, or for the amelioration of theeffects caused by trauma to a subject, the formulation comprising fourbiologically active compounds from four respective groups of compounds,in amounts that are pharmaceutically effective for each compound,respectively, when administered in combination with the other threebiologically active compounds. Four-component formulations of theinvention comprise at least one biologically active compound from thegroup comprising anticonvulsants and antiepileptics, wherein theanticonvulsant or antiepileptic is at least one form of pregabalin, atleast one biologically active compound from the group comprisingneurosteroids and neuroactive steroids, wherein the neurosteroid orneuroactive steroid is at least one form of progesterone or syntheticprogestin, at least one biologically active compound from the groupcomprising NK-1 receptor antagonists wherein the NK-1 receptorantagonist is aprepitant, and at least one biologically active compoundfrom the group comprising lithium-containing and lithium-relatedcompounds wherein the lithium-containing or lithium-related compound isat least one form of lithium carbonate.

In its many preferred four-component embodiments, the present inventioncomprises formulations adapted for the prevention of the development ofneuropathology and neurodegeneration, or for the amelioration of theeffects caused by trauma to a subject, the formulation comprising fourbiologically active compounds from four respective groups of compounds,in amounts that are pharmaceutically effective for each compound,respectively, when administered in combination with the other threebiologically active compounds. Four-component formulations of theinvention comprise at least one biologically active compound from thegroup comprising anticonvulsants and antiepileptics, wherein theanticonvulsant or antiepileptic is at least one form of gabapentin, atleast one biologically active compound from the group comprisingneurosteroids and neuroactive steroids, wherein the neurosteroid orneuroactive steroid is at least one form of progesterone or syntheticprogestin, at least one biologically active compound from the groupcomprising NK-1 receptor antagonists wherein the NK-1 receptorantagonist is aprepitant, and at least one biologically active compoundfrom the group comprising lithium-containing and lithium-relatedcompounds wherein the lithium-containing or lithium-related compound isat least one form of lithium carbonate.

Many dosages, dosage ranges and combinations of the essential fourcomponents of the present four-component formulations are within thescope and spirit of the invention. As one of many preferred embodiments,in a four-component formulation of the invention, the pregabalin isprovided in a dosage range of from about 0.5 mg to about 2,400 mg, theprogesterone or synthetic progestin is provided in a dosage range offrom about 0.05 mg to about 1,200 mg, the aprepitant is provided in adosage range of from about 0.05 to about 750 mg, and the lithiumcarbonate is provided in a dosage range of from about 0.5 mg to about3,600 mg.

Many dosages, dosage ranges and combinations of the essential fourcomponents of the present four-component formulations are within thescope and spirit of the invention. As one of many preferred embodiments,in a four-component formulation of the invention, the gabapentin isprovided in a dosage range of from about 5.0 mg to about 9,600 mg, theprogesterone or synthetic progestin is provided in a dosage range offrom about 0.05 mg to about 1,200 mg, the aprepitant is provided in adosage range of from about 0.05 to about 750 mg, and the lithiumcarbonate is provided in a dosage range of from about 0.5 mg to about3,600 mg.

In another preferred embodiment of a four-component formulation for usewith the methods and procedures of the invention, pregabalin is providedin a dosage range of from about 15 mg to about 1,200 mg, progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg, aprepitant is provided in a dosage range of from about 5to about 375 mg, and lithium carbonate is provided in a dosage range offrom about 30 mg to about 1,800 mg. As a further alternative preferredembodiment of the present methods and procedures, a four-componentformulation consists essentially of pregabalin provided in a dosagerange of from about 25 mg to about 600 mg, progesterone or syntheticprogestin provided in a dosage range of from about 50 mg to about 450mg, aprepitant provided in a dosage range of from about 20 to about 250mg, and lithium carbonate is provided in a dosage range of from about100 mg to about 900 mg.

In another preferred embodiment of a four-component formulation for usewith the methods and procedures of the invention, gabapentin is providedin a dosage range of from about 50 mg to about 4,800 mg, progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg, aprepitant is provided in a dosage range of from about 5to about 375 mg, and lithium carbonate is provided in a dosage range offrom about 30 mg to about 1,800 mg. As a further alternative preferredembodiment of the present methods and procedures, a four-componentformulation consists essentially of gabapentin provided in a dosagerange of from about 100 mg to about 2,400 mg, progesterone or syntheticprogestin provided in a dosage range of from about 50 mg to about 450mg, aprepitant provided in a dosage range of from about 20 to about 250mg, and lithium carbonate is provided in a dosage range of from about100 mg to about 900 mg.

As yet another preferred embodiment of the present four-componentmethods and procedures, a formulation for use in the methods andprocedures of the invention consists essentially of pregabalin providedin a dosage range of from about 50 mg to about 150 mg, progesterone orsynthetic progestin provided in a dosage range of from about 100 mg toabout 300 mg, aprepitant provided in a dosage range of from about 40 toabout 120 mg, and lithium carbonate provided in a dosage range of fromabout 200 mg to about 600 mg.

As yet another preferred embodiment of the present four-componentmethods and procedures, a formulation for use in the methods andprocedures of the invention consists essentially of gabapentin providedin a dosage range of from about 200 mg to about 600 mg, progesterone orsynthetic progestin provided in a dosage range of from about 100 mg toabout 300 mg, aprepitant provided in a dosage range of from about 40 toabout 120 mg, and lithium carbonate provided in a dosage range of fromabout 200 mg to about 600 mg.

Depending on the specific use and therapeutic context, analogues ormodifications to the specific compounds included in embodiments of thisinvention can be tailored to target specific cells, tissues, organs,biological processes or pathways or to facilitate access of compounds totarget sites in the central, peripheral or enteric nervous systems.

In accordance with yet other objects of the invention, a formulation ofthe invention may comprise a single dosage unit, or may be administereda plurality of times in a sequence, and to further achieve its objects,the formulation may be administered to a subject one or more dosageunits per day. The present formulations, methods procedures and meansare of the invention, the formulation is given to a subject mammal inneed, wherein the subject is human.

As will be understood by one of ordinary skill in the art without undueexperimentation, compounds in the formulations may be in the form of oneor more of salts, prodrugs, hydrates, derivatives or metabolites of thecompound itself, analogs, homologs, compounds acting on or throughmechanisms that compounds can act on or through or compounds thatmodify, modulate or affect in any way pathways or processes affected bycompounds or formulations of the invention.

One or more of the compounds in the formulation may be in a controlledrelease or slow release form, and formulations of the invention may beadapted and arranged to be administered as one or more sustaining doses.As yet another advantageous characteristic, formulations of theinvention may be adapted and arranged to be administered before, during,or after a traumatic event or in anticipation of a possible traumaticevent.

Also in accordance with the present invention, administration of theformulation to a mammal in need thereof can be effected with respect totime in order to advantageously intervene with negative processes orevents triggered by the trauma, or in order to stimulate processes orevents useful in correcting or ameliorating the damage triggered by thetrauma. This timing can thus be in relation to one or more of i.) theonset of the trauma, ii.) in anticipation of a possible or potentialtrauma, iii.) during the trauma, and iv.) during a period of recoveryfrom the trauma.

In one preferred embodiment, the presently disclosed formulations arefirst administered within two hours after the traumatic event. Inalternative embodiments, the present formulations are first administeredwithin 24 hours after the trauma. In yet another preferred embodiment,the presently disclosed formulations are first administered preventivelyor prophylactically within 6 hours before the expected onset or theexpected end of the trauma.

Moreover, formulations of the invention can be administered additionallyone, or a plurality of, times after the formulation is firstadministered. In a similar manner, the present formulations can beadministered one, or a plurality of times as a sustaining dose asneeded.

Particular Advantages of Invention Embodiments

The present disclosed technology presents and illustrates at least fourparticular advantageous aspects of the invention embodiments, togethercomprising formulations, methods and procedures for reducing orpreventing the development or the risk of development of neuropathologyand neurodegeneration as a result of traumatic injury.

One particular advantageous aspect of embodiments of the inventionincludes the formulations of the presently disclosed technology, whichformulations comprise two or more pharmaceutical compounds from fourfamilies of chemical compounds, administered together or sequentially atclinically effective doses. In general, each chemical compound, orentity, in the formulation is theorized to target a different biologicalprocess or different biological processes that is or are involved ingoverning the degree of secondary injury that follows a primarytraumatic injury. Alternatively stated, some components of theformulations are directed at optimizing or facilitating the restorativeprocesses that follow, or are triggered by, a primary traumatic injury.Some components of the formulation are directed at minimizing orinhibiting the degenerative processes that follow or are triggered by aprimary traumatic injury. As described herein, restorative processeslead to recovery and, in contrast, degenerative processes lead to tissuedamage and cell death. Applicant posits that optimal treatment toprevent or reduce secondary injury is best achieved by a multi-drugapproach to include promotion of a number of different restorativeprocesses and in addition inhibition of a number of differentdegenerative processes. The present disclosed technology and itsembodiments are directed at maximizing control of the processes thatgovern eventual functional outcomes of trauma and neuropathology andneurodegeneration.

Before the present invention, the particular combinations of compoundsdescribed herein that make up or constitute the present formulationswere unknown. Evidence of the efficaciousness of single-compoundtreatments for neurotrauma is spotty or contradictory. Hindsight withrespect to the field of neurotrauma hints only generally towardsingle-component remedies, and not to any particular combination ofdrugs to possibly be selected from the various categories ofpharmaceuticals and myriad permutations possibly selectable from them.Nonetheless, Applicant posits that the formulations, methods andprocedures of the presently disclosed invention are effective inreducing or preventing the development of, or the degree of, or the riskof development of, neuropathology and neurodegeneration as a result oftrauma.

Despite the fact that single compound administrations in the art havehad only limited, or no, beneficial effects, Applicant posits that amulti-drug approach that is directed at one or a plurality ofrestorative and degenerative processes, as is exemplified by the presentformulations, may have greater beneficial effects than those derivingfrom a single-compound approach.

A second particular advantageous aspect of the invention embodiments isthe specific treatment modality, wherein a formulation of the inventionis given in temporal relation as a preventive, prophylactic orposttraumatic event treatment. The preventive practice aspects of thepresent invention is in cases where there is a high risk of trauma to anindividual or there is planned entry into a condition, situation orplace where such high risk may ensue. Prophylactic practice of theinvention is in cases where incidence studies inform a known probabilitythat that a procedure or practice results in neuropathology in a givennumber of subjects or patients. Posttraumatic event practice of theinvention is in cases where a traumatic event has occurred or isoccurring. In all cases, the presently disclosed technology is directedat preventing or reducing, or reducing the risk of, such neuropathologyand neurodegeneration as a result of trauma.

A third particular advantageous aspect of the methods and formulationsof the invention embodiments is the timing and route of administration,coupling the formulations and the delivery to the means of administeringa formulation in a time-effective practice. Timing and route ofadministration of the formulations thus can be adapted and arranged toaccommodate specific and unique conditions, situations, severity andtype of trauma, and the status of the subject/recipient. As one example,in the event of unanticipated trauma, which may occur away from ahospital/clinic setting, at-site immediate or earliest possibleadministration of the formulation can be by nasal administration toprovide a fast and effective intervention in an easily and sociallyacceptable format. Delivery by intranasal administration may also be bynasal spray, or by any effective means and methods effective to addressthe specific trauma, or class or class of trauma. In the context of anevent of an anticipated trauma, for example, one that occurs in ahospital/clinic setting, treatment with a formulation can be intranasaladministration but can alternatively be by oral, buccal, intravenous oreven intramuscular routes.

A fourth particular advantageous aspect of the invention embodimentsdirects the formulations, the methods and the procedures specifically atsecondary injury resulting from any and all types of trauma. This aspectof the invention is in contrast to the conventional view that thespectrum of types of trauma to the nervous system is not typically orusually considered as a single medical issue. To illustrate this point,standard emergency or immediate treatment of brain injury and stroke aredifferent and follow different standard protocols and procedures.However, while the primary trauma may be different, the processes andmechanisms of the secondary injury that can and often do ensue from bothconditions are the same. Brain injury and stroke are thought to triggerthe same, similar or overlapping restorative mechanisms and, similarly,they both trigger the same, similar or overlapping degenerativemechanisms. Advantageously, treatment by the present means and methodscould be the same, similar or overlapping for both stroke and TBI. Thepresent fourth particular advantageous aspect of the inventionembodiments is in some respect that the formulations, methods andprocedures can be applied universally or broadly for many types oftrauma to the nervous system. As examples, practice of the invention isthe same, similar or overlapping for metabolic trauma, such as from anepileptic seizure, and for impact or concussion trauma, such as from apenetrating head wound; similarly, trauma from chemotherapy or radiationtherapy is believed to trigger the same, similar or overlappingneuropathological processes. Further, trauma is treated with the samepractices of the invention whether trauma is to the periphery, to theenteric nervous system or to the central nervous system. Treatingtrauma-induced neuropathology as a single entity presents the framework,then, for practice of the present invention to fill the gap betweenstandard emergency practice and standard rehabilitation practice, asdescribed herein.

There is an additional aspect, or advantage, of the presently disclosedinvention embodiments. Because trauma to the brain is known to increasethe risk of the later development of some degenerative disorders, thepresently disclosed technology is also directed at reducing orpreventing the risk of longer-term neurodegeneration. To substantiatethis point, head trauma is a risk factor for Parkinson's disease; strokeis a risk factor for Alzheimer's disease. As detailed herein, headtrauma and stroke trigger the same, similar or overlapping cascades ofprogressing restorative and degenerative processes that alter thehealth, function and survival of nerves, nerve cells, neural supportcells and neural support tissues, and, as these cascades are shared bytrauma of different types the presently disclosed formulations, methodsand procedures are useful in reducing risk factors for neurodegenerativediseases such as but not limited to Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, multiple sclerosis, subacuteposttraumatic ascending myelopathy and the like.

Addressing the Multiplicity of Theorized Underlying Processes

In one aspect, the presently disclosed technology is based particularlyon a polypharmacy, or a multi-drug, approach wherein delivery ofbeneficial chemical entities is given at specific times following oreven before trauma. Current conventional approaches to treattrauma-induced neuropathology have heretofore focused exclusively onsingle drug approaches. Further, current approaches to treattrauma-induced neuropathology have focused uniquely on eitherrestorative processes or degenerative processes. Even further, there isreticence to initiate clinical trials due to the complexity and costdemanded by treating a number of independent injury factorssimultaneously that occur over a prolonged period of time followingtrauma. Applicant posits that efforts to develop effective therapeuticapproaches to minimize negative sequelae of trauma have failed becauseof failure to accommodate the multiplicity of the events triggered bytrauma and a failure to match this multiplicity with appropriateadditive or synergistic multi-drug approaches. The presently disclosedtechnology and its embodiments are directed to address this unsolvedneed by evidence-based potentially synergistic formulations that promoterecovery and restoration and at the same time inhibit or prevent loss ofcell function and cell death.

Applicant posits further that the progressive nature of these cascadesof events in secondary injury may inform why conventional attempts totreat such injuries have failed to prevent the long-term adverse healthsequelae of trauma-induced neuropathology and neurodegeneration. Incontrast to conventional attempts, the present formulations are directedto addressing multiple underlying physiological mechanisms involved inthe development of secondary injury triggered by traumatic events.

Any traumatic injury results in a localized initial direct damageaccompanied by impaired regulation of blood flow and metabolism, usuallywith an ensuing edema swelling. Direct physical damage to nerve cells,neural support cells and neural support tissues can result, for example,from tearing, shearing, stretching or compression of nervous tissue.These events triggered directly by the traumatic event are usuallytreated clinically by hypothermia and efforts to reduce blood pressureas well as pharmacologically with drugs such as mannitol andbarbiturates, largely to decrease mortality. What is not included instandard practice is effort or action to prevent or reduce the secondaryinjury resulting form the initial trauma even though long-termdisability results mainly from secondary in many victims of trauma.Standard immediate treatment of traumatic injury does not typicallyinclude steps to reduce or prevent or alter the plethora of secondaryinjury mechanisms that are triggered within minutes and hours of atraumatic event.

Some processes of secondary injury are activated immediately by atraumatic even. Some progress over a limited period of time and thenreturn to pre-injury levels, while other processes may continue fordays, weeks or months. Some processes are cascades, one step triggeringa subsequent step or subsequent steps in a myriad of metabolic andbiochemical pathways. It is important to point out that once the initialprocesses have been completed any medical interventions for thetreatment of the persisting adverse outcomes of traumatic injury arelargely without benefit. As a result, from the time of a traumatic eventthere is a closing window of opportunity to reduce or prevent thedevelopment or the risk of development of neuropathology as a result oftraumatic injury and that there is a platinum hour, a golden day and asilver week of opportunity to achieve optimal outcomes.

Secondary Injury as an Unaddressed Crisis

Unfortunately for those who are victims of trauma-inducedneuropathology, standard immediate treatment strategies do not includeneuroprotection. Immediate pre-hospital management of trauma focuses onsuch issues as airway clearance, prevention of hypoxia, hypercapnia andhypotension, as well as rapid transport to a medical center for detaileddiagnosis and treatment. Actions to limit or prevent secondary injury tonerves, nerve cells or neural support cells or neural support tissuesare absent from standard pre-hospital practice. As one example, in arecent review, while a stated purpose of the report was to focus onlimiting secondary brain injury, there was no reference to directapproaches to limit neuropathology and neurodegeneration from secondaryinjury; in this case secondary brain injury had a different meaning fromthat used here and the focus was on emergency services without anyregard for neuroprotection. Applicant posits that treatment withformulations given at doses shown to be safe for acute administrationcan be given at-site before complete diagnosis has been carried out.Applicant posits further that in some cases formulations given at dosesshown to be safe for acute administration should be given immediately,without waiting for complete diagnosis to be carried out.

As a further example, in a recent report based on 119 cases of traumaticbrain injury to military personnel injured by anti-personnel devices orby vehicle landmines, specific recommendations were made based on theoutcomes of various management approaches, including immediatebattlefield management as well as subsequent hospital management. Therewas no recommendation for any action or procedure to provideneuroprotection from secondary brain injury resulting from the trauma.Similarly, recent recommendations for medical management followingimprovised explosive device accidents did not include any action orprocedure to provide neuroprotection from secondary injury.

Clinical treatment of penetrating brain injury, as yet another example,typically consists of reducing increased intracranial pressure andreducing brain edema through surgical decompression, removal of anyforeign bodies, administration of osmotic agents and reducing bodytemperature. Immediate standard treatment does not include steps toreduce or prevent the developing secondary injury.

In the case of spinal injury, immediate medical practice includessurgical decompression and stabilization in order to reduce edema and toprevent further primary injury. However, a retrospective observationalstudy concluded that surgical treatment has not resulted in improvedhospital mortality or length of stay and a consensus meeting concludedthat surgery does not improve neurological outcome. Clearly, currentstandard practice is not meeting need. With 1200 new cases of spinalcord injury in the US each year, there is an urgent medical need tominimize the impact of injury on victims, on the healthcare system andon the economy.

Standard practice for trauma of any type, then, does not include stepsor actions to minimize secondary injury. The result in many cases isunnecessary disability. Rehabilitation is the domain for management ofdisability. Applicant posits that secondary injury can be prevented orreduced. Further, Applicant posits that the incidence and the severityof disability can also be prevented or reduced by including in standardemergency practice application and practice of the presently disclosedtechnology.

Addressing Unsolved and Unaddressed Needs

Incidence studies indicate the number of people in a population who willgo on to develop disability following trauma of any given type. Untilthe presently disclosed invention, these numbers have been accepted asbeing inevitable. There is a general acceptance that disability resultsfrom trauma. Applicant believes that this does not need to be the case.Medical attention has not typically been directed at reducing thesenumbers, especially preventing them altogether. Yet, as described hereinmuch of the disability that ensues as a result of trauma is broughtabout by processes, largely biochemical, which can be modified byappropriate pharmaceutical intervention. Trauma-induced disability canthus be considered an unsolved need. Applicant posits that the number ofpeople who go on to develop disability following trauma can be reduced.Further, Applicant posits that the severity of disability of those thatdo develop some level of disability can be reduced. The scope and thespirit of the presently disclosed invention embodiments are directedtoward this unsolved need, both by reducing the number of victims oftrauma that go on to develop adverse health conditions and disability,as well as by reducing the severity of disability in those who are leftwith trauma-induced negative or adverse health conditions. In accordancewith this and other objects, the presently disclosed technology, incertain specific embodiments, aims to prevent or reduce the development,or the risk of development, of neuropathology that results fromtraumatic injury.

Numerous approaches have been taken to understand the variety ofdifferent mechanisms of secondary injury in both human and animalstudies. With respect to drug therapy the literature contains severalreviews of the area in the past few years. However, a consensus in thesereviews is that despite at least 20 compounds being tested in over 50trials by the year 2004, and over 30 phase III prospective clinicaltrials by 2010, significant endpoints have not been reached by anytherapeutic intervention and no effective drug therapy is currentlyavailable. This failure can be attributed to a number of causes; even ifa drug passes phase III clinical trials, full benefit may be elusivebecause all drugs currently in clinical trials II and III aremonotherapies and do not address the consensus of the thought leaders inthe field that the multiplicity of mechanisms contributing to secondaryinjury require a polypharmacy, or multi-drug, approach. The criticalliterature attributes much of the failure to bring effectiveinterventions forward from phase III clinical trials to the fact thatmost such trials, and their antecedent development strategies, aredirected at a single factor or mechanism, despite the awareness of theplurality of the underlying mechanisms.

Further, mechanisms leading to this injury and its ensuing disabilityare complex and occur over a period of time extending up to months oreven years after the traumatic event. Consensus opinion in the field isthat a multi-mechanistic approach is needed, where multiple activecompounds are given simultaneously or synchronously over specifiedrespective periods of time. This is in stark contrast to the protocolsof current clinical trials; these are based on monotherapies directed atonly a limited number of the plethora of mechanisms that govern theseverity of neuropathology and thereby the incidence and severity of thedisability sequelae.

Applicant believes that at present, current drug development does notaddress the pluralities of treatment that are needed and, further, thatstandard practice that is immediate and even rehabilitation standardpractice totally miss the underlying fact that there is a “platinumhour,” a “golden day” and a “silver week,” when the adverse healthconditions, and the disability resulting from trauma-inducedneuropathology and neurodegeneration, can be reduced or prevented andthat a multi-drug approach is needed.

Unexpectedly, Applicant has recognized the significance of theheretofore unknown possible synergy of selected combinations ofcompounds that include formulations of two, three or four compounds fromthe four categories of anticonvulsant/antiepileptics,neurosteroids/neuroactive steroids, NK-1 receptor antagonists andlithium-containing/lithium-related compounds. These combinations areadapted and arranged, and adaptable and arrangeable, to facilitate,promote or potentiate the restorative processes that lead toneurological recovery, while at the same time lessening, or inhibiting,the degenerative processes that lead to secondary, progressive tissuedamage and cell death.

While the bases for the possible synergistic advantages of the presentformulations have been heretofore unknown, as have been the presentcombinations, the formulations are directed toward modifying bothrestorative and degenerative processes. Embodiments of the invention aredirected with the proposition that improved neurological outcomes thatare known to result from trauma can be reduced or prevented, or the riskof such outcomes, can be reduced or prevented by the administration of aformulation of possibly synergistic compounds that combine neurotrophicactions that repair and restore, as well as neuroprotective actions thatprevent or reduce degenerative processes that lead to secondary injuryor damage.

Applicant posits that three important issues need to be addressed inorder to arrive at effective medical intervention that will optimallyreduce or prevent secondary brain injury resulting from brain or headtrauma. One issue is the target or targets at which an intervention isaimed. Optimally, effective therapeutic intervention would promote,facilitate or potentiate restorative or regenerative targets and willalso inhibit, lessen or block targets involved in further injury, lossof function and cell death. A second issue is that, given themultiplicity of the biochemical, metabolic and cellular mechanismscausing secondary brain injury, multiple targets need to be included inany effective therapeutic intervention. The third is that, given thetemporal dispersal of the cascade of biochemical, metabolic and cellularevents, the timing of various components of the intervention iscritical, as well as the sequencing of the multiple therapeuticinterventions. These three issues are addressed in the presentlydisclosed technology, which, along with its embodiments, includesevidence-based formulations, methods and procedures to reduce or preventthe development or the risk of development of neuropathology andneurodegeneration as a result of traumatic injury.

All types of trauma are known to activate secondary injury mechanisms.These secondary injury mechanisms are brought about as the outcome of abalance of restorative and degenerative biochemical and other processestriggered by trauma. The biochemical nature of these processes providesinroads to pharmaceutical intervention that can reduce or even preventthe alteration of function and even the death of nerve cells and theirneural support cells and neural support tissues, alterations that canand often do ultimately lead to adverse health conditions or disability.The presently disclosed technology, in its numerous embodiments, isdirected to promote these restorative processes and to inhibit thesedegenerative processes by specific pharmaceutical intervention atappropriate doses, with specific timings and sequences of intervention,using specific routes and modes of delivery.

Many traumatic events are unexpected and unanticipated such as sportsconcussions and battlefield injuries to the head. However, in many casestraumatic events can be anticipated, events that can and often do leadto adverse health conditions and disability. For example, clinical andincidence studies provide supportive evidence that as a result ofcertain procedures or events there is a high incidence of adverse healthconditions and disability. A person having ordinary skill in the artwill recognize that prophylactic measures can be taken in conditionswhere there is a high enough probability of neuropathology resultingfrom a clinical procedure. Further, in situations or conditions where atraumatic event may occur that can lead to damage or injury to nervecells, to neural support cells or to neural support tissues, thatprecautionary or preventive measures are warranted, as described herein.The scope and spirit of the presently disclosed technology and itsembodiments are directed toward both: unanticipated as well asanticipated traumatic injury.

Some examples are provided to illustrate what is meant as anticipatedand unanticipated traumatic events. Minor head injury events are usuallyunanticipated, and have been reported to lead to restrictions inlifestyle one year later in 47% of admissions to hospital. Chronic paincaused by surgery varies according to the type of surgery, butcontinuing pain one year after amputation has been reported in up to 85%of patients. Further, medically induced sensory, motor, autonomic orenteric nerve damage can and often does occur as a result ofchemotherapy or radiation therapy. Spinal cord injury is usuallyunanticipated, and some survivors can be expected to have permanentphysical disabilities, reduced independence, serious medicalcomplications and enormous financial burden. Stroke is usuallyunanticipated, but in view of the fact that an estimated 44 milliondisability-adjusted life-years are lost by stroke survivors worldwide,many who have had a stroke know that they are at risk of a subsequentstroke or subsequent strokes. Applicant posits that much of the adversehealth conditions and disability resulting from these and all traumasare amenable to therapeutic intervention.

As described herein, each of the chemical entities in a formulation ofembodiments of the invention is theorized to target one or morebiological processes or mechanisms. Applicant theorizes that some ofthese mechanisms may sometimes be involved in governing the incidenceand the degree or severity of secondary injury that follows the primarytraumatic injury. It is at this secondary injury that the formulationsof the invention embodiments are directed. A great amount ofinvestigation regarding individual members of the categories ofcompounds has produced no efficacious formulations or methods. Indeed, agreat amount of research in the field of neuropathology does not supportaspects of Applicant's theory regarding the efficacy of particularcombinations and dosages of these categories of compounds. This is soespecially because, in some cases, administration of single compoundsseldom produces adequate benefit, if any, and sometimes causes harm.

Despite this, Applicant presents novel formulations and methods havingutility in treating various types and forms of neuropathology. In somesense, selected literature in the field might support the view that someof the individual compounds discussed herein, such as theneurosteroids/neuroactive steroids andlithium-containing/lithium-containing/lithium-related drugs, would beeffective in promoting, facilitating or potentiating restorativeprocesses due to, or resulting from, trauma.

In a similar sense, selected literature in the field might support theview that some anticonvulsant/antiepileptics and somelithium-containing/-lithium-containing/lithium-related drugs, might actto minimize or inhibit degenerative processes that follow or aretriggered by a primary traumatic injury. Again, attempts at using thesecompounds have failed to provide sufficiently efficacious solutions toneuropathological conditions, although some single-compound attemptshave shown some benefit.

Applicant has recognized the significance of the heretofore unknowncomplementarity of selected combinations of compounds that includeformulations of two, three or four compounds from the four categories ofanticonvulsant/antiepileptics, neurosteroids/neuroactive steroids andlithium-containing/lithium-containing/lithium-related compounds and NK-1receptor antagonists. These combinations are adapted and arranged, andadaptable and arrangeable, to facilitate, promote or potentiate therestorative processes that lead to neurological recovery, while at thesame time lessening, or inhibiting, the degenerative processes that leadto secondary, progressive tissue damage and cell death.

While the bases for any possible synergistic advantages of the presentformulations have been heretofore unknown, as have been the presentcombinations, the formulations are directed toward modifying bothrestorative and degenerative processes. Embodiments of the invention aredirected with the proposition that neurological outcomes that resultfrom trauma can be reduced or prevented, or the risk of such outcomescan be reduced or prevented, by the administration of a formulation ofcompounds that combine neurotrophic actions to repair and restore, aswell as neuroprotective actions to prevent or reduce the incidence andseverity of secondary injury or damage that results from trauma.

DETAILED DESCRIPTION OF THE INVENTION

Numerous combinations, variations and permutations of preferredformulations of the invention can be provided while remaining within thescope, spirit, function and effectiveness of the invention. Among themany preferred four-component formulations are those wherein theanticonvulsant/antiepileptic is pregabalin, the neurosteroid/neuroactivesteroidal agent is progesterone or synthetic progestin, the NK-1receptor antagonist is aprepitant and thelithium-containing/lithium-containing/lithium-related compound islithium carbonate.

Numerous combinations, variations and permutations of preferredformulations of the invention can be provided while remaining within thescope, spirit, function and effectiveness of the invention. Among themany preferred four-component formulations are those wherein theanticonvulsant/antiepileptic is gabapentin, the neurosteroid/neuroactivesteroidal agent is progesterone or synthetic progestin, the NK-1receptor antagonist is aprepitant and thelithium-containing/lithium-containing/lithium-related compound islithium carbonate.

Preferred dosages of the respective compounds are many, and include anythat produce the required or desired effect with respect to theparticular trauma or traumas. As one of skill in the art can appreciate,such dosages can be tailored with respect to many factors. Exemplary ofthese factors are the nature and extent of the trauma, the cause of thetrauma, the tissues affected by the trauma, the time since the traumaticevent, whether the traumatic event is continuing or ongoing, the currentmedications being taken by the subject, if any, the standard or otheremergency medical procedures being applied to the subject at the time,the proximity to, need for, and range of care of a specializedhealthcare facility, such as a hospital or emergency clinic, as well asthe size, gender, race, ethnicity, age and physical condition of thesubject mammal, especially humans.

As one of skill in the art will comprehend, the formulations of theinvention described herein include those wherein one of the fourcompounds can be provided in a number of ranges, while the relativeamounts the remaining three components of the invention in the specifiedranges can be determined by methods known generally in thepharmaceutical art.

Among these formulations, wherein the range amount of one component isdefined, are those wherein the pregabalin is provided in specifieddosage ranges. As examples of preferred ranges of pregbalin, a dosagerange of from about 0.5 mg to about 2,400 mg. is provided. Similarly, apreferred dosage range of the pregabalin component can be provided in adosage range of from about 15 mg to about 1,200 mg. A more preferreddosage range is where the pregabalin is provided in a dosage range offrom about 25 mg to about 600 mg. In a most preferred dosage range thepregabalin can be provided in a dosage range of from about 50 mg toabout 150 mg.

Among these formulations, wherein the range amount of one component isdefined, are those wherein the gabapentin is provided in specifieddosage ranges. As examples of preferred ranges of gabapentin, a dosagerange of from about 5.0 mg to about 9,600 mg. is provided. Similarly, apreferred dosage range of the gabapentin component can be provided in adosage range of from about 50 mg to about 4,800 mg. A more preferreddosage range is where the gabapentin is provided in a dosage range offrom about 100 mg to about 2,400 mg. In a most preferred dosage rangethe gabapentin can be provided in a dosage range of from about 200 mg toabout 600 mg.

Similarly, among these formulations are those wherein the progesteroneor synthetic progestin is provided in set dosage ranges while theamounts of the other components are determined relative to those ranges.Exemplary of these are wherein the progesterone or synthetic progestinis provided in amounts of from about 0.05 mg to about 1,200 mg. Inanother preferred dosage range, the progesterone or synthetic progestinis provided in a range of from about 5 mg to about 600 mg. A morepreferred dosage range is where the progesterone or synthetic progestinis provided in a dosage range of from about 50 mg to about 450 mg. In amost preferred dosage range the progesterone or synthetic progestin isprovided in a dosage range of from about 100 mg to about 300 mg.

With respect to lithium-containing/lithium-related compounds, among theformulations that are initially defined by one component are thosewherein the lithium carbonate is provided in a preferred dosage range offrom about 0.5 to about 3,600 mg. In a more preferred dosage range thelithium carbonate is provided in a dosage range of from about 30 mg toabout 1,800 mg. A more preferred dosage range is where the lithiumcarbonate is provided in a dosage range of from about 100 mg to about900 mg. In a most preferred dosage range the lithium carbonate isprovided in a dosage range of from about 200 mg to about 600 mg.

Particular Four-Component Formulations

As yet another advantage of the invention, many preferred four-componentformulations of the invention are provided wherein each of the fourcomponents is provided in a specified range. Among these preferredformulations are those wherein the pregabalin is provided in a dosagerange of from about 0.5 mg to about 2,400 mg, wherein the progesteroneor synthetic progestin is provided in a dosage range of from about 0.05mg to about 1,200 mg, and wherein the lithium carbonate is provided in adosage range of from about 3.0 to about 3,600 mg. Another preferredformulation comprises wherein the pregabalin is provided in a dosagerange of from about 15 mg to about 1,200 mg, wherein the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg, and wherein the lithium carbonate is provided in a dosagerange of from about 30 mg to about 1,800 mg.

As yet another advantage of the invention, many preferred four-componentformulations of the invention are provided wherein each of the fourcomponents is provided in a specified range. Among these preferredformulations are those wherein the gabapentin is provided in a dosagerange of from about 5.0 mg to about 9,600 mg, wherein the progesteroneor synthetic progestin is provided in a dosage range of from about 0.05mg to about 1,200 mg, and wherein the lithium carbonate is provided in adosage range of from about 3.0 to about 3,600 mg. Another preferredformulation comprises wherein the gabapentin is provided in a dosagerange of from about 50 mg to about 4,800 mg, wherein the progesterone orsynthetic progestin is provided in a dosage range of from about 5 mg toabout 600 mg, and wherein the lithium carbonate is provided in a dosagerange of from about 30 mg to about 1,800 mg.

Other preferred formulations of the invention include wherein thepregabalin is provided in a dosage range of from about 25 mg to about1,200 mg, wherein the progesterone or synthetic progestin is provided ina dosage range of from about 50 mg to about 450 mg, and wherein thelithium carbonate is provided in a dosage range of from about 100 mg toabout 900 mg; and wherein the pregabalin is provided in a dosage rangeof from about 50 mg to about 150 mg, wherein the progesterone orsynthetic progestin is provided in a dosage range of from about 100 mgto about 300 mg, and wherein the lithium carbonate is provided in adosage range of from about 200 mg to about 600 mg.

Other preferred formulations of the invention include wherein thegabapentin is provided in a dosage range of from about 100 mg to about2,400 mg, wherein the progesterone or synthetic progestin is provided ina dosage range of from about 50 mg to about 450 mg, and wherein thelithium carbonate is provided in a dosage range of from about 100 mg toabout 900 mg; and wherein the gabapentin is provided in a dosage rangeof from about 200 mg to about 600 mg, wherein the progesterone orsynthetic progestin is provided in a dosage range of from about 100 mgto about 300 mg, and wherein the lithium carbonate is provided in adosage range of from about 200 mg to about 600 mg.

Formulations of the invention can be provided in many types of dosages,and in many types of dosage units, including those in which the releaseof the individual compounds is controlled, slowed, delayed or sequencedin accordance with the desired delivery dynamics of the formulation withrespect to many factors as known in the art. The many formulations ofthe invention can thus be adapted and arranged with respect to, asexamples, the characteristics and circumstances of the subject, thenature and extent of the trauma, and the nature and extent of theoverall injury. These factors include, as additional examples, theenvironment in which they are intended to be used, the intended users,the liquid, solid or other form in which the formulation is provided,the intended subjects or recipients, the type of trauma, the proximityand need for specialize healthcare such as a hospital or emergencyclinic, the age, body weight and gender of the subject, and othermedications the subject may be receiving.

In some preferred embodiments, a formulation of the invention comprisesa single dosage unit. In other preferred embodiments, two, or aplurality, of dosages are provided over time with respect to the onset,or with respect to the anticipated onset, of the traumatic event.Formulations of the invention can be provided also in many types ofcontrolled release forms adapted for providing effective amounts of eachof the compounds of the formulations at appropriate times.

The various dosing regimens and timing sequences with respect toadministration of the formulation can be configured such that aneffective treatment for the prevention, amelioration, or post-traumaticmanagement, of the neuropathological sequelae associated with trauma toa subject comprises the administration of one or more dosage units perday. As examples of factors to be considered in this regard, are thesubject's vital signs, the subject's state of consciousness, theseverity of the trauma, and other medications the subject may be taking.

In other advantageous aspects of the invention, formulations of theinvention can be developed, titrated, configured, adapted and arrangedwith respect to one or more sets of dosage ranges for one or all of thefour components or compounds of the formulation. As one example, theanticonvulsant/antiepileptic, such as pregabalin, can be provided in adosage range of from about 0.5 mg to about 2,400. Mg. The dosages anddosage ranges of the other three biologically active compounds can thenbe adapted to correspond to the chosen dosage level of the pregabalin.Thus, by using a set range for one, two or three of the four compoundsof a formulation of the invention, the effectiveness of the overallformulation can be determined with respect to the chosen one, two orthree compounds.

In other advantageous aspects of the invention, formulations of theinvention can be developed, titrated, configured, adapted and arrangedwith respect to one or more sets of dosage ranges for one or all of thefour components or compounds of the formulation. As one example, theanticonvulsant/antiepileptic, such as gabapentin, can be provided in adosage range of from about 5.0 mg to about 9,600. Mg. The dosages anddosage ranges of the other three biologically active compounds can thenbe adapted to correspond to the chosen dosage level of the gabapentin.Thus, by using a set range for one, two or three of the four compoundsof a formulation of the invention, the effectiveness of the overallformulation can be determined with respect to the chosen one, two orthree compounds.

Thus, in a similar manner, the neurosteroid/neuroactive steroidcompound, such as progesterone or synthetic progestin, can be providedin a dosage range, for example, of from about 50 mg to about 450 mg. inorder to accomplish a similar evaluation. Moreover, theLithium-containing/lithium-containing/lithium-related compound of theformulation, such as lithium carbonate, can be provided in a dosagerange of from about 100 mg to about 900 mg.

Formulations of the invention can be provided in any effective form. Asexamples, formulations of the invention can be provided wherein one ormore of the compounds is in the form of one or more of salts, prodrugs,hydrates, derivatives or metabolites of a compound itself, analogs,homologs, compounds acting on or through mechanisms that compounds canact on or through or compounds that modify, modulate or affect in anyway pathways or processes affected by compounds or formulations of theinvention.

Moreover, formulations of the invention can be provided wherein one ormore of the biologically active compounds are provided in at least onecontrolled release form. In addition, formulations of the invention canalso be adapted and arranged to be administered as one or moresustaining doses. Similarly, the disclosed formulations can be adaptedand arranged to be administered before a possible or an anticipatedtraumatic event.

While not intending to be bound by any one theory or set of theories, inone underlying aspect, Applicant speculates that the formulations of theinvention possess unexpected advantages in part because they do not relyon affecting just one neurological mechanism. Instead, Applicantbelieves that the present formulations are adapted and arranged toaffect several restorative, as well as several degenerative, underlyingmechanisms. Alternatively stated, some of the components of the presentformulations are selected to maximize the recovery processes initiatedby the trauma, while other components are selected to minimize orprevent the destructive processes initiated by that same trauma. Indoing so, formulations of the invention are believed to achievecomplementary positive effects that would not be achieved byformulations that affect only one of the involved mechanisms. Moreover,Applicant speculates that the specific formulations disclosed herein areespecially effective when compared to other multiple-drug approaches.

Particular Method Embodiments

In accordance with similar and parallel objectives of the invention, amethod for the prevention of, for reducing the effects of, or forreducing the risk of development of neuropathology and neurodegenerationincident to trauma, is provided.

In one preferred embodiment, a method of the invention comprises thesteps or actions of Step A) providing a formulation adapted for theprevention of the development of neuropathology, wherein the formulationcomprises four biologically active compounds in amounts that arepharmaceutically effective for each compound, respectively, whenadministered in combination with the other three biologically activecompounds, the four compounds comprising a pharmaceutically effectiveamount of: i) at least one biologically active compound from the groupcomprising anticonvulsant and antiepileptic drugs, ii) at least onebiologically active compound from the group comprising neurosteroids andneuroactive steroids, iii) at least one biologically active compoundfrom the group comprising NK-1 receptor antagonists, and iv) at leastone biologically active compound from the group comprisinglithium-containing and lithium-related compounds, and wherein theformulation is in a form adapted and arranged for administration to amammal in need thereof, such that the development, or the risk ofdevelopment, of neuropathology and neurodegeneration is reduced,lessened, attenuated or prevented; and Step B) administering theformulation to a mammal in need thereof.

In accordance with a particularly advantageous aspect of the invention,Step B of the method is preferably effected with respect to time inrelation to one or more of i) the onset of the trauma, ii) inanticipation of the trauma, iii) during the trauma, and iv) during aperiod after the trauma. A method of the invention thus affords widechoices with respect to adapting and arranging the administration of aformulation of the invention with respect to the time of the onset andduration of the trauma, as well as with respect to a possible or anexpected trauma.

A method of the invention thus encompasses wherein the formulation isfirst administered posttraumatic event within one hour after the onsetof the trauma, or within two hours after the onset of the trauma, orwithin three hours after the onset of the trauma, or within six hoursafter the onset of the trauma, or within 8 hours after the onset of thetrauma, or within 12 hours after the onset of the trauma, or within 18hours after the onset of the trauma. or within 24 hours after the onsetof the trauma or within two days, or within three, four, five, six orseven days or any time thereafter.

In some preferred embodiments, the method of the invention includes alsowherein the formulation is administered at least once when a subject isabout to enter into a situation, condition or scenario where trauma mayoccur, in which case this is a preventive measure as described herein.Examples of such preventive administration include within 10 hoursbefore the possible onset of the trauma, within 8 hours before thepossible onset of the trauma, or within 6 hours before the possibleonset of the trauma, or within 4 hours before the possible onset of thetrauma, or within 2 hours before the possible onset of the trauma or atthe time of onset of the trauma.

In some preferred embodiments, the method of the invention includes alsowherein the formulation is administered at least once in anticipation orexpectation of trauma, or prophylactically as described herein. Examplesof such prophylactic administration, include within 10 hours before theexpected onset or the expected end of the trauma within 8 hours beforethe expected onset or the expected end of the trauma, or within 6 hoursbefore the expected onset or the expected end of the trauma, or within 4hours before the expected onset or the expected end of the trauma, orwithin 2 hours before the expected onset or the expected end of thetrauma or at the time of onset of the expected or possible trauma.

As an additional advantageous aspect of the method of the invention,formulations of the invention can be administered more than one time.Additional administrations can be provided one or a plurality of timesafter the formulation is first administered regardless of whether aformulation is first administered before, during or after the trauma. Ina similar manner, formulations of the invention can be administered one,or a plurality of times as desired or needed, as one or more sustainingdoses in order to provide desired physiological or pharmacologicallevels in the subject of the several compounds of the formulations.

As a particularly preferred aspect of the present method, theformulation is configured such that the at least oneanticonvulsant/antiepileptic is pregabalin, the at least oneneurosteroid/neuroactive steroid is progesterone or synthetic progestin,and the at least onelithium-containing/lithium-containing/lithium-related compound islithium carbonate.

As a particularly preferred aspect of the present method, theformulation is configured such that the at least oneanticonvulsant/antiepileptic is gabapentin, the at least oneneurosteroid/neuroactive steroid is progesterone or synthetic progestin,and the at least onelithium-containing/lithium-containing/lithium-related compound islithium carbonate.

Preferred dosages of the respective formulations and compounds to beused in the present method are many, and include any that produce therequired or desired effect with respect to the particular trauma ortraumas. As one of skill in the art can appreciate, such dosages can betailored with respect to many factors. Exemplary of these factors arethe nature and extent of the trauma, the cause of the trauma, thetissues affected by the trauma, the time since the traumatic event,whether the traumatic event is continuing or ongoing, the currentmedications being taken by the subject, if any, the standard or otheremergency medical procedures being applied to the subject at the time,the proximity to, need for, and range of care of a specializedhealthcare facility, such as a hospital or emergency clinic, as well asthe size, gender, race, ethnicity, age and physical condition of thesubject mammal, especially humans.

Among these formulations are those wherein the pregabalin is provided ina dosage range of from about 0.5 mg to about 2,400 mg. In a preferreddosage range the pregabalin is provided in a dosage range of from about15 mg to about 1,200 mg.

Among these formulations are those wherein the gabapentin is provided ina dosage range of from about 5.0 mg to about 9,600 mg. In a preferreddosage range the gabapentin is provided in a dosage range of from about50 mg to about 4,800 mg.

Among these formulations are those wherein the progesterone or syntheticprogestin is provided in a dosage range of from about 0.05 mg to about1,200 mg. In a preferred dosage range the progesterone or syntheticprogestin is provided in a dosage range of from about 5 mg to about 600mg.

Among these formulations are those wherein the lithium carbonate isprovided in a dosage range of from about 0.5 to about 3,600 mg. In apreferred dosage range the lithium carbonate is provided in a dosagerange of from about 30 mg to about 1,800 mg.

Other preferred dosages of compounds and formulations suitable for usein effecting the method of the invention are listed elsewhere in thepresent disclosed invention and its embodiments, both textually and inthe Tables presented elsewhere in this disclosed invention and itsembodiments. As one of skill in the art can appreciate, any of thepresent formulations can be configured, adapted or arranged for use withthe present method in conjunction with any of the dosage ranges of anyor all of the other constituents of the formulations.

Scope of the Invention

The foregoing detailed description sets forth various embodiments offormulations, methods, procedures and practices for reducing orpreventing the development, or the risk of development, ofneuropathology and neurodegeneration as a result of traumatic injury.Insofar as such formulations, methods, procedures and practices containone or more functions or operations, it will be understood by thosewithin the art that each formulation, method, procedure and practice canbe implemented, individually or collectively, within a wide range ofmany combinations without undue experimentation.

The present invention provides heretofore unknown advantages in thetreatment and prevention and reduction of trauma-induced damage andinjury to nerve cells or neural support cells or neural support tissues.The presently disclosed technology and its embodiments aim to fill a gapin standard practice for treating victims of trauma. This is the gap, asdescribed herein, that exists between standard emergency practice andstandard rehabilitation practice. This gap represents an unsolvedmedical need. The presently disclosed technology aims to fill this gap.

The presently disclosed technology focuses on reducing the negativeconsequences that can and frequently do follow or ensue from trauma. Inthe context of invention embodiments, a traumatic event causes a primaryinjury to tissues including nerve cells, neural support cells or neuralsupport tissues. Cell loss caused by this primary injury is beyondtreatment. However, the injury to neural tissues in the area of thisprimary injury spreads through secondary injury mechanisms in time aswell as to neighboring and even remote cells and tissues, includingnerve cells, neural support cells and neural support tissues, that donot die from this primary injury. Indeed, the damage caused by thesesecondary processes can be as serious and extensive as, or even moreserious and extensive than, that caused by the primary trauma. Secondaryprocesses also progress over time so that injury and damage can continueover the days, weeks and even months after the initial injury. Further,the secondary processes can also progress spatially so that injury anddamage can spread to other parts of the body and manifest at sitesremote from the site of the primary trauma, whether in the brain,brainstem, spinal cord, enteric nervous system or peripheral nervoussystem.

This balance can be tipped toward normal function and health byappropriate pharmaceutical intervention at the appropriate time. Thiscan be achieved because of the chemical nature or basis of therestorative and degenerative processes occurring at the cellular,biochemical and metabolic levels.

Restorative mechanisms: as detailed herein there are many targets orpoints of entry for pharmaceutical promotion, facilitation orpotentiation of restorative processes to tip this balance towardfunction and health, in order to reduce or prevent the loss of function,the adverse health conditions or the disability that can and often doresult from a traumatic event. The presently disclosed technology andits embodiments are based on a select few targets or points of entry, asrepresented in the formulations of the presently disclosed technology.This selection of specific, additive or synergistic compounds of theformulations is based on fundamental and clinical evidence detailedherein and elsewhere that is available and understood by a person havingordinary skill in the art.

Degenerative mechanisms: as detailed herein there are many targets orpoints of entry for pharmaceutical inhibition, lessening or blocking thedegenerative processes that tip this balance away from function andhealth toward loss of function, adverse health conditions or disability.Such an approach is taken in order to reduce or prevent the loss offunction, the adverse health conditions or the disability that can andoften do result from a traumatic event. The presently disclosedtechnology and its embodiments are based on a select few targets orpoints of entry to reduce the degenerative processes, as represented inthe formulations of the presently disclosed technology. This selectionof specific, additive or synergistic compounds of the formulations isbased on fundamental and clinical evidence detailed herein and elsewherethat is available and understood by a person having ordinary skill inthe art.

Conventional or standard immediate or emergency treatment of traumatypically consists of minimizing the symptoms of the immediate, orprimary, traumatic injury. In significant contrast, the primary aspectof the presently disclosed technology does not focus on either reducingthe immediate trauma or rehabilitating long-term disability once thisdisability has been established. Instead, embodiments of the inventionare directed toward the sequelae of post-trauma effects that are anindirect result of the primary trauma. The aim is to incorporate thepresently disclosed technology into standard emergency health care, aswell as to practice the presently disclosed invention as standardpreventive and prophylactic practice.

Significantly, a point of differentiation between conventional orstandard methods and the presently disclosed technology is thedifference between the treatment of the symptoms of the primary injury,and formulations, methods and procedures taken at or about the time oftrauma to prevent or lessen damage from the secondary sequelae that,without the benefit of the presently disclosed technology, may or arelikely to occur. Thus, an important aspect of the presently disclosedtechnology is its usefulness in treating to prevent injuries that areexpected or likely to occur, but that are not the damage causedimmediately and directly by a traumatic event. Alternatively stated, thepresently disclosed technology is distinguished by its prevention oramelioration of the secondary sequelae versus the treatment of theprimary injury.

Secondary injury spreads to sites remote from the primary injury. Infact, the cascades of mechanisms leading to secondary injury at remotesites are also triggered locally at the site of the primary injury. Thepresently disclosed technology aims to reduce or prevent this secondaryinjury irrespective of whether this manifests locally or more remotely.

Conventional rehabilitation treatment is aimed at ameliorating existingsymptoms, adverse health conditions or disability caused by the primaryinjury. These typical existing symptoms are easily recognized and can bemeasured. In significant contrast is the presently disclosed technology,where prevention is aimed at symptoms that are neither existent norpresent at the time immediately following a traumatic event, but whichhave a likelihood to manifest if not reduced or prevented based onknowledge of their incidence with respect to the category of primaryinjury.

As indicated herein, the cascades of mechanisms leading to secondaryinjury are triggered within hours yet continue to occur over the ensuingdays, weeks and months. As a result, symptoms of secondary injurymanifest over such periods, and the presently disclosed technology aimsto reduce or prevent the manifestation or expression of these symptomsof secondary injury, which are known on the basis of incidence studiesto occur. As a result, the presently disclosed technology addressessymptoms that are non-apparent, but that can be expected to occur with aknown incidence if not reduced or prevented by appropriatepharmaceutical intervention.

Despite this, it is known with certainty that trauma activates secondaryinjury mechanisms in a significant percentage of victims or patients.What can be measured with respect to these secondary injuries, then, isthe incidence, measured at later time points after a category oftraumatic events, by comparisons that can be made. Such comparisons aremade, as examples, of the number of people who, after a category oftraumatic events, show symptoms that typically manifest long term inindividuals that have been treated by standard procedures alone, withthe number of people showing symptoms that are observed in individualsthat have been treated by standard procedures along with theadministration of formulations of the presently disclosed technology inaccordance with embodiments of the presently disclosed technology.

Similarly, comparisons can be made of the severity of the symptoms thattypically manifest after a category of traumatic event in thoseindividuals that have been treated with standard procedures alone, withthe severity of symptoms in those treated with standard procedures alongwith the practice of invention embodiments, including administration offormulations of the presently disclosed technology and the methods andprocedures as described herein.

(i) The presently disclosed technology and its particular embodimentsprovide numerous formulations that comprise combinations ofcomplementary existing chemical entities that have not been combined asin the presently disclosed technology. In one aspect, the specificchemical entities included in formulations of invention embodiments areselected along informed and rationalized lines of thought derived froman understanding of the intrinsic mechanisms that are triggered byprimary injury and an understanding of the mechanisms of the secondarysequelae of this primary injury.

(ii) The biological targets of embodiments of formulations providedherein include mechanisms of the secondary sequelae that are restorativeand function to restore neurons, neural support cells and neural supporttissues toward their condition before the trauma and as well includemechanisms of the secondary sequelae that are degenerative processes,which drive neurons, neural support cells and neural support tissuestoward pathology, or loss of function or even cell death. Formulationsof invention embodiments are therefore advantageous for the providedcombination of specific chemical entities that, combined, reduce orprevent, or reduce the risk of, secondary damage indirectly resultingfrom, or triggered by, the trauma event.

(iii) The present disclosure provides new uses of each of the chemicalentities in the formulations of invention embodiments. Evidence is citedin the description of the invention supporting the current uses of eachof the families of chemical entity that are included in the formulation.There is some evidence that certain members of each of the four classesof chemical entity may have some neuron-sparing effect, but to datethese have not been used to reduce or prevent, or reduce the risk, ofsecondary injury to nerve cells, to neural support cells and neuralsupport tissues and to endothelial cells resulting from trauma.

(iv) The formulations are advantageous also in that they are directed atmaximizing, potentiating or facilitating naturally-occurring restorativemechanisms, while at the same time minimizing, reducing or inhibitingnaturally-occurring degenerative processes. There is currently nomedical intervention that purposefully targets both restorative anddegenerative processes that are triggered by trauma and that govern,recover from or lead to secondary injury to nerve cells, neural supportcells and neural support tissues or endothelial cells.

(v) The presently disclosed technology is advantageous in that theformulations target trauma-induced secondary injury to nerve cells.Further, the presently disclosed technology also targets trauma-inducedsecondary injury to neural support cells and neural support tissues.Even further, the presently disclosed technology also targetstrauma-induced secondary injury to endothelial cells. As loss offunction of neural support cells and neural support tissues andendothelial cells can contribute to overall secondary injury to nervecells, protection of injury to neural support cells and neural supporttissues and endothelial cells is also included in the presentlydisclosed technology.

(vi) The presently disclosed technology is advantageous in that ittargets secondary injury to nerve cells, to neural support cells andneural support tissues, and to endothelial cells resulting fromphysical, chemical, metabolic, medical, surgical or other trauma. Thepresently disclosed technology outlines the various forms that each ofthese types of trauma manifests and the presently disclosed technologydescribes how the formulations, methods and procedures of the presentlydisclosed technology will prevent or reduce, or reduce the risk of,secondary injury to nerve cells, to neural support cells and neuralsupport tissues, and to endothelial cells, that results from braininjury, ischemia of the central nervous system, spinal cord injury,enteric nervous system injury or peripheral nerve injury. It is theintent of the presently disclosed technology to include the fullspectrum of trauma and traumatic events that lead to secondary injury tonerve cells, to neural support cells and neural support tissues, and toendothelial cells inclusive of all parts of the body.

(vii) There is evidence from animal studies that early intervention atthe time of trauma reduces the incidence as well as the severity of longterm functional deficits. In one important aspect, the presentlydisclosed technology is advantageous in that it directs specificformulations to administration to humans.

(viii) The presently disclosed technology is advantageous in that aformulation is to be given beginning at specific times before, at thetime of or immediately following trauma, and continued as needed.

(ix) The presently disclosed technology is advantageous in that itspecifies that a formulation is to be given differently depending on thesetting, which is described for purposes of illustration but notlimitation, as the home setting, the pre-hospital setting, or anysetting outside the home and outside a hospital or sufficiently equippedclinical setting, where pre-medic or medic intervention is possible, anda hospital or clinical setting that is fully staffed and equipped forthe full range of healthcare.

(x) The presently disclosed technology is advantageous in that itspecifies the timing of administration of the formulation, dependingupon the specific setting, as referred to in herein.

(xi) The presently disclosed technology is advantageous in that theroute of administration is dependent upon the specific setting, asdefined herein and as in examples of the particular embodiments.

(xii) The presently disclosed technology is advantageous in that theformulations are applied differentially for unanticipated vs.anticipated trauma as described herein. Medical interventions orprocedures, including those described herein, can lead to neuropathologyand neurodegeneration. With respect to anticipated trauma, the presentlydisclosed technology is directed to reduce the known incidence ofneuropathology and neurodegeneration as outlined herein, and therebyreduce the known long term disability and loss of function that resultfrom the medical interventions described herein. The presently disclosedtechnology is advantageous in reducing or preventing, or reducing therisk, of injury to nerve cells, neural support cells and neural supporttissues, and endothelial cells that occurs or can occur as a result ofsurgical or other medical interventions or procedures.

All types of trauma, including those addressed in the presentlydisclosed technology extract a heavy toll on individuals, on families,on the health care system and on the economy. These types of traumainclude, as examples but are not limited to, brain injury, centralnervous system ischemia, spinal cord injury, enteric nervous systeminjury and peripheral nerve injury. Primary injuries resulting fromthese types of trauma are not amenable to prevention or reduction, butthe secondary processes triggered by the primary trauma are, with thebenefit of the presently disclosed technology and its embodiments,amenable to medical intervention.

Exemplary Practice Embodiments of the Invention

The formulations, methods, procedures and systems of the presentlydisclosed technology provide a significant number of combinations offormulations, formulation components, dosages, administration sequences,patterns and combinations thereof to offer efficacious and safeanticipatory (pre-trauma) and posttrauma treatments for secondary damageor injury to nerve cells, neural support cells or neural supporttissues.

To illustrate some of these permutations, Applicant presents herein someexamples of the many particular embodiments of the invention, whilenoting that a person having ordinary skill in the art, armed with thepresent disclosure, would be able to comprehend and practice numerousforms of the formulations, methods, procedures and systems of inventionembodiments, while adapting them to specific uses and circumstances andcan do so without undue experimentation.

By way of scientific background, and as further described herein, allnerve cells, neural support cells and neural support tissues undergosimilar or overlapping changes as a result of trauma, irrespective ofwhether these neurons are in the brain, the brainstem, the cerebellum,the spinal cord, or in the enteric nervous system or the periphery. Theterminology “trauma” is broadly interpreted as explicated in itsdefinitions and delineations as described herein.

The same or similar or overlapping restorative and degenerativeprocesses, as defined herein, are triggered in nerve cells, neuralsupport cells or neural support tissues, by trauma, irrespective of thesite or the type of neuron or cell. While there may be some minordifferences, such as the difference in sensitivity to excitotoxicity ofneurons in the hippocampus vs. neurons in the cerebral cortex, thephysiological processes triggered by trauma are believed to be the same,or quite similar or overlapping, in all neurons.

These physiological processes, including both the restorative and thedegenerative processes, are activated within seconds or minutes by atraumatic event, and continue to develop over the hours and daysfollowing the trauma. Each change that is activated or triggered bytrauma sets off a process or cascade of biochemical and metabolicchanges, as detailed herein. As a person having ordinary skill in theart will understand, as a result of the activation of degenerativeprocesses, it is advised that treatment be initiated at the earliestpossible time in order to arrest or prevent further changes along thecascade. Similarly, it is advised that the restorative processes orcascades be facilitated or promoted to counteract the degenerativecascades and processes, and before irreparable damage can be done to thenerve cells, neural support cells or neural support tissues. The view ofthe Applicant is that there is a platinum hour, a golden day and asilver week within which optimal protection from trauma andneuropathology can be achieved, especially in the contexts of thepresently disclosed technology and its embodiments. If allowed toprogress, much of the neuropathology is entrenched and cannot beprevented or reversed, leading to permanent adverse health conditions ordisability.

Whether the invention embodiments are practiced with respect to braininjury, central nervous system ischemia, spinal cord injury, entericnervous system injury or peripheral nerve injury practice of theinvention, as indicated herein with examples of particular embodiments,occurs within the same or similar treatment parameters. As detailedherein, a key aspect of the invention in some particular embodimentsrelates to the timing of the administration of one or more of thepresent formulations. In accordance with this aspect, the timing of theadministration of formulations of the invention is preferably adaptedand arranged with respect to the traumatic event itself. Thus, thepractice of the invention can be before a traumatic event has occurredor after a traumatic event has occurred. This timing aspect can bedescribed generally with respect to three situations in which manyembodiments of the invention are to be practiced: A) precautionaryadministration, B) prophylactic administration and C) posttraumaticevent administration. Specific examples are provided herein toillustrate these three types of practice of invention embodiments, butare presented as examples only and do not exclude other practices of theinvention.

Precautionary practice of invention embodiments includes, situationswhere an individual is about to enter into a high-risk situation orcondition where trauma may occur. Precautionary practice would be anexigent practice, exigent circumstance practice, or contingency practiceand is different from prophylactic practice or posttraumatic eventpractice.

Embodiments of the invention are useful also in circumstances where atrauma is quite likely to occur, or whenever it is even anticipated.Embodiments of the invention that are precautionary in nature are quiteuseful, and fill a void which presently exists with respect to thetreatment or prevention of trauma-induced neuropathology andneurodegeneration in high risk conditions or situations.

In such cases of great likelihood of trauma being soon endured by one ormore individuals, the presently disclosed technology is uniquelyapplicable. In such cases, no traumatic event has yet occurred at thetime that a formulation of invention embodiments is taken by a subjector administered to a subject. In such precautionary embodiments of themethods, procedures, means and systems of embodiments of the invention,a formulation is administered before the highly expected trauma event orat the time of the pre-trauma awareness that a potential trauma exists.

In some embodiments lithium is not included in the usual four-componentformulation because of its relatively narrow therapeutic dose range andthe relatively low threshold for adverse effects. In other words,lithium is not included unless there is an actual traumatic event, inwhich case practice of the invention will follow the formulationsmethods and procedures represented herein as posttraumatic eventpractice embodiments

Prophylactic practice of invention embodiments includes situations wherea procedure, particularly a medical procedure, is about to take placewherein the procedure is known to produce, or where evidence indicates acertain probability that it may produce, trauma, damage or injury tonerve cells or neural support cells or neural support tissues in somepatients, whether in the central nervous system, the peripheral nervoussystem or the enteric nervous system. Prophylactic practice is thusdistinguishable from precautionary practice or posttraumatic eventpractice.

Embodiments of the invention are useful in medical circumstances whereevidence from clinical studies indicates a certain probability thatdamage to nerves or nerve cells, or neural support cells or neuralsupport tissues may result from a medical procedure, such as surgery orother medical treatment or medical procedure, for example but notexclusive to chemotherapy or radiation therapy. Embodiments of theinvention that are prophylactic in nature are quite useful, and fill avoid which presently exists with respect to the prevention ofneuropathology that may result from surgery or medical treatment ofmedical procedure. Embodiments of the invention include types ofsituations or scenarios where there is known or substantiated evidencethat neuropathology, or damage to nerve cells, or neural support cellsor neural support tissues may be or will be an outcome of surgery orother medical treatment or medical procedure in some patients.

Posttraumatic event practice of invention embodiments includes anysituation or condition where a traumatic event is occurring or hasoccurred, and there is known, or there is reason to suspect, damage,injury or cell death to nerve cells, neural support cells and neuralsupport tissues, whether in the central nervous system, the peripheralnervous system or the enteric nervous system. Posttraumatic practice isthus distinguished from precautionary practice or prophylactic practice.

Embodiments of the invention are useful in circumstances where atraumatic event has taken place and there is trauma or suspected traumato the central nervous system, the peripheral nervous system or theenteric nervous system, comprising any neuron, set of neurons, nerve ornerve cell, or any cell or tissue that supports the health or survivalof nerve cells directly or indirectly.

Embodiments of the invention that are posttraumatic in nature are quiteuseful, and fill a void which presently exists with respect to thetreatment or prevention of neuropathology, or the risk of neuropathologythat may result from a traumatic event.

In such posttraumatic embodiments of the methods, procedures, means andsystems of embodiments of the invention, the formulation is administeredas soon as possible after the traumatic event has occurred. In cases ofan on-going or continuing traumatic event, the formulation isadministered during the traumatic event or as soon afterward aspossible. Administration of the formulation is continued as needed.

Therapeutic Advantages Particularly Associated with the DisclosedMulti-Agent Formulations

Applicant anticipates that multi-agent formulations, as disclosedherein, will provide substantial therapeutic advantages over existingtherapeutic formulations related to the agents included in suchformulations, which, so far as applicant is aware, are single activeagent formulations. Applicant anticipates that the coincidenttherapeutic use of multiple agents as disclosed herein, covering a rangeof mechanisms of action, will provide therapeutic benefits forparticular neurological conditions, as disclosed herein, thatsubstantially exceed the benefits that could be ascribed to the use ofany single agent alone. With reference to therapeutic benefits in excessof those that could be derived from any single agent, alone, theenhancement due to combination therapy could be additive or it could besynergistic. By additive, it is meant that the total benefit of amulti-agent formulation exceeds that which could be maximally achievedby any single agent as a monotherapy, regardless of the maximaleffective dose of any single agent. By synergistic, it is meant that thetotal benefit of a multi-agent formulation exceeds even that which mightbe expected from adding the maximal therapeutic benefits from each ofthe agents as a monotherapy.

Applicant further anticipates that the dosage-response profiles ofindividual agents, when administered in multi-agent formulations asprovided herein, and for the conditions as described herein, may beleft-shifted. By left-shifted, it is meant that that maximal effectivedosages of individual agents in multi-agent formulations may be lowerthan dosages required for maximal therapeutic effect when the individualagents as used as a monotherapy. The use of lower dosages of theindividual agents may advantageous in terms of minimizing unwanted sideeffects of the agents that are associated with high dosages of theagent, particularly when used as a monotherapy. Lower dosages alsoprovide a clear economic advantage to such multi-agent formulations.

Another aspect of therapeutic or safety advantages of the presentlydisclosed multi-agent formulations relates to minimizing the possibilityof abusive uses of individual agents. Some anti-convulsants, such asbarbiturates and benzodiazepines, have a burden of being used as drugsof abuse or recreational use. In practical terms, including drugs ofpotential abuse within a multi-agent formulation tends to discourage itsrecreational or abusive use.

Coformulation of multiple agents, as provided herein offers stillfurther therapeutic advantages over monotherapy in that sequential andtimed release strategies may be usefully applied to individual agentswithin the multi-agent formulation. The many uses and advantages ofsequential or timed-release formulations are discussed elsewhere in thisdisclosure. For example, it may be advantageous to stage thepharmacodynamics of agents, as disclosed herein, independently of eachother. By way of particular example, it may be advantageous for thecirculatory profiles of individual agents to be temporally staged withrespect to each other (one agent having a circulatory profile thatprecedes the profile of a second agent). Such level of therapeuticchoreography is significantly more controllable in multi-agentformulations delivered as a single pill, rather than multiplemonotherapeutic formulations being delivered in separate pills.

TABLE 1 Dosage Ranges Of Constituents Of Formulations RepresentingParticular Embodiments Of The Invention More Most Acceptable PreferablePreferable Preferable Compound Range (mg) Range (mg) Range (mg) Range(mg) Pregabalin 0.5-2,400 50-1,200 25-600   50-150 Gabapentin  5-9,60050-4,800 100-2,400 200-600 Progesterone 0.02-600   0.2-300   2-100100-300

Dosage ranges for constituents of formulations are based to some extenton ranges of standard practice and are intended as exemplary, and notlimiting. Instead, they are provided as additional guidance with respectto the invention embodiments, although those of skill in the art willcomprehend with certainty that specific dosages, or specific dosageranges, can be determined with respect to many other combinations andpermutations with the assistance of the present Specification andprocedures known in the art which can be adapted without undueexperimentation.

A person having ordinary skill in the art will recognize that, in onesignificant aspect, the herein described formulations (e.g., anycombination of pregabalin and progesterone or synthetic progestin),methods, and procedures and practices, and the discussion accompanyingthem, are used as examples for the sake of conceptual clarity and thatvarious methods, procedures and practices are within the skill of thosein the art. Consequently, as used herein, the specific exemplars setforth and the accompanying discussion are intended to be representativeof their more general classes. In general, use of any specific exemplarherein is also intended to be representative of its class, and thenon-inclusion of such specific formulation components (e.g., pregabalin,progesterone or synthetic progestin and lithium), methods, andprocedures and practices herein should not be taken as indicating thatlimitation is desired.

A person having ordinary skill in the art will recognize that, in onesignificant aspect, the herein described formulations (e.g., anycombination of gabapentin and progesterone or synthetic progestin),methods, and procedures and practices, and the discussion accompanyingthem, are used as examples for the sake of conceptual clarity and thatvarious methods, procedures and practices are within the skill of thosein the art. Consequently, as used herein, the specific exemplars setforth and the accompanying discussion are intended to be representativeof their more general classes. In general, use of any specific exemplarherein is also intended to be representative of its class, and thenon-inclusion of such specific formulation components (e.g., gabapentin,progesterone or synthetic progestin and lithium), methods, andprocedures and practices herein should not be taken as indicating thatlimitation is desired.

It is generally contemplated that the formulations according to theinventive subject matter will be formulated for administration to amammal, and especially to a human, having a condition that is responsiveto the administration of such a formulation. Therefore, wherecontemplated formulation compounds are administered in a pharmacologicalcomposition, it is understood that contemplated compounds can beformulated in admixture with pharmaceutically acceptable carriers. As anexample but not exclusively, contemplated compounds can be administeredorally as pharmacologically acceptable salts, or intravenously in aphysiological saline solution (e.g., buffered to an appropriate pH suchas about 7.2 to 7.5). Conventional buffers such as phosphates,bicarbonates or citrates can be used for this purpose. Of course, one ofordinary skill in the art may modify the formulations within theteachings of the present disclosure to provide numerous formulations fora particular route of administration.

In particular, contemplated compounds may be modified to render themmore soluble in water or other vehicle that, for example, may be easilyaccomplished with minor modifications (e.g. salt formulation,esterification, etc.) that are well within the ordinary skill in theart. It is also well within the ordinary skill of the art to modify theroute of administration and dosage regimen of a particular compound orformulation in order to manage the pharmacokinetics of the presentcompounds for maximum beneficial effect in a patient or subject.

In particular, contemplated compounds may be prepared for delivery intablet, capsule, pill or solution form, including any form that candeliver a controlled release of these compounds.

Similarly, it should be appreciated that while some claims recitecomponents of formulations of invention embodiments, one of skill in theart will comprehend that other constituents, while pharmacologicallyinactive or inert in the context of the presently disclosed technology,might be a part of the formulation. Such inactive constituents include,as examples, excipients, binders, coatings, absorption enhancers,penetration enhancers, transport enhancers, stabilizers, chelators,buffers, carriers, clearance modifiers, emulsifying agents,antioxidants, preservatives, sugars, salts, cellulose, dyes, flavoringagents and any other inactive ingredients that are considered generallyrecognized as safe.

In certain pharmaceutical dosage forms, prodrug and derivative forms ofcontemplated compounds may be formed for various purposes, includingreduction of toxicity, increasing the organ or target cell specificity,etc. Among various prodrug and derivative forms, acylated (acetylated orother) derivatives, pyridine esters and various salt forms of thepresent compounds may be advantageous. One of ordinary skill in the artwill recognize how to readily modify the present compounds to prodrugand other forms to facilitate delivery of active compounds to a targetsite within the host organism or patient. One of ordinary skill in theart will also take advantage of favorable pharmacokinetic parameters ofthe prodrug and other forms, where applicable, in delivering the presentcompounds to a targeted site within the host organism, subject orpatient to maximize the intended effect of the formulation.

Similarly, it should be appreciated that contemplated compounds may alsobe metabolized to their biologically active form (e.g., viahydroxylation, glycolsylation, oxidation etc.), and all metabolites ofthe compounds herein are therefore specifically contemplated. Inaddition, contemplated compounds (and combinations thereof) may beadministered in combination with yet further antiviral and/orantibacterial agents. Suitable additional drugs therefore include butare not limited to various antibiotics (e.g., beta-lactam antibiotics,tetracycline antibiotics, oxazine antibiotics, etc.), various antiviralcompounds (e.g., polymerase inhibitors), and/or compounds that stimulatethe immune system.

With the presently disclosed technology described in detail herein, itis to be understood that the invention is not limited to the particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments, and is not intended to be limiting,since the scope of the presently disclosed technology will be limitedonly by the appended claims or by a fair reading of the application as awhole.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within embodiments of the invention. Theupper and lower limits of these smaller ranges may independently beincluded in the smaller ranges is also encompassed within embodiments ofthe invention, subject to any specifically excluded limit in the statedrange. Where the stated range includes one or both of the limits, rangesexcluding either or both of those included limits are also included inembodiments of the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which embodiments of this invention belongs. Although anymethods and materials similar or equivalent to those described hereincan also be used in the practice or testing of the presently disclosedtechnology, a limited number of the exemplary methods and materials aredescribed herein.

All publications mentioned herein are hereby incorporated by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited, as well as the general background forthe inventive subject matter disclosed herein. The publicationsdiscussed herein are provided solely for their disclosure prior to thefiling date of the present application. Nothing herein is to beconstrued as an admission that the presently disclosed technology is notentitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided might be different from theactual publication dates, which may need to be independently confirmed.

The inventive technology described herein sometimes illustratesdifferent components contained within, or connected with, differentother components. It is to be understood that such descriptions orsubject matter are merely exemplary, and that in fact many otherdescriptions, examples, methods, procedures and practices can beimplemented which achieve the same functionality. In a conceptual sense,any arrangement of components to achieve the same functionality iseffectively “associated” or “coupled” such that the desiredfunctionality is achieved. Hence, any two or more methods, procedures orpractices herein combined to achieve a particular functionality can beseen as “associated with” each other such that the desired functionalityis achieved, irrespective of condition, event, injury, damage orpathology components. Likewise, any two or more components so associatedcan also be viewed as being “operably connected”, or “operably coupled”,to each other to achieve the desired functionality, and any two or morecomponents capable of being so associated can also be viewed as being“operably couplable”, to each other to achieve the desiredfunctionality. Specific examples of operably couplable include but arenot limited to, practices of embodiments of the invention required underdifferent conditions, practices of embodiments of the inventionrequiring different routes or methods of administration, practices ofembodiments of invention requiring repeated administration for varyingperiods of time or logically interacting or logically interactablecomponents to achieve the desired functionality.

In a general sense, those skilled in the art will recognize that thevarious aspects described herein which could be implemented,individually or collectively, by a wide range of methods, procedures orpractices, or any combination thereof, can be viewed as being composedof various types of “formulation.” Consequently, as used herein“formulation” includes, but is not limited to, two compounds selectedfrom pregabalin and progesterone or synthetic progestin, three compoundsselected from pregabalin, progesterone or synthetic progestin andlithium or four compounds selected from pregabalin, progesterone orsynthetic progestin, an NK-1 receptor antagonist and lithium. Thosehaving skill in the art will recognize that the subject matter describedherein may be implemented in a method, procedure or practice asdescribed herein, or some combination thereof.

In a general sense, those skilled in the art will recognize that thevarious aspects described herein which could be implemented,individually or collectively, by a wide range of methods, procedures orpractices, or any combination thereof, can be viewed as being composedof various types of “formulation.” Consequently, as used herein“formulation” includes, but is not limited to, two compounds selectedfrom gabapentin and progesterone or synthetic progestin, three compoundsselected from gabapentin, progesterone or synthetic progestin andlithium or four compounds selected from gabapentin, progesterone orsynthetic progestin, an NK-1 receptor antagonist and lithium. Thosehaving skill in the art will recognize that the subject matter describedherein may be implemented in a method, procedure or practice asdescribed herein, or some combination thereof.

As examples, the formulations, methods, procedures or practices ofcertain embodiments of the invention include many combinations andpermutations thereof with respect to the nature of the individualformulations, and their relative methods, procedures or practices, canvary in operation by the relative methods, procedures or practices.

While particular aspects of the present subject matter described hereinhave been shown and described, it will be apparent to those skilled inthe art that, based upon the embodiments herein, changes andmodifications may be made without departing from the subject matterdescribed herein and its broader aspects and, therefore, the appendedclaims are to encompass within their scope all such changes andmodifications as are within the true spirit and scope of the subjectmatter described herein.

Those skilled in the art will recognize that it is common within the artto describe methods, procedures or practices in the fashion set forthherein, and thereafter use standard practices to integrate suchdescribed methods, processes or procedures to reduce or prevent thedevelopment or the risk of development of neuropathology as a result oftraumatic injury. That is, at least a portion of the methods, proceduresor practices described herein can be integrated into reducing orpreventing the development or the risk of development of neuropathologyas a result of traumatic injury via a reasonable amount ofexperimentation. Those having skill in the art will recognize thattypical methods, procedures or practices generally include thosedescribed herein. A typical method, procedure or practice may beimplemented utilizing any suitable commercially available instrument,tool or device, such as any typically found in a medical facility orhealth delivery context or venue, and available to those typicallyfamiliar with methods, procedures or practices generally applied bythose skilled in the art.

With respect to the use of substantially any plural or singular termsherein, those having skill in the art can translate from the plural tothe singular or from the singular to the plural as is appropriate to thecontext or application. The various singular/plural permutations are setforth herein for sake of clarity.

Furthermore, it is to be understood that the invention is defined by theappended claims, and by the many claims that could be supported by thepresent specification. It will be understood by those within the artthat, in general, terms used herein, and especially in the appendedclaims (e.g., bodies of the appended claims) are generally intended as“open” terms (e.g., the term “including” should be interpreted as“including but not limited to,” the term “having” should be interpretedas “having at least,” the term “includes” should be interpreted as“includes but is not limited to,” etc.). It will be further understoodby those within the art that if a specific number of an introduced claimrecitation is intended, such an intent will be explicitly recited in theclaim, and in the absence of such recitation no such intent is present.For example, as an aid to understanding, the appended claims may containusage of the introductory phrases “at least one” and “one or more” tointroduce claim recitations. However, the use of such phrases should notbe construed to imply that the introduction of a claim recitation by theindefinite articles “a” or “an” limits any particular claim containingsuch introduced claim recitation to inventions containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations.

It will be further understood by those within the art that virtually anydisjunctive word or phrase presenting two or more alternative terms,whether in the description, claims, or practices, should be understoodto contemplate the possibilities of including one of the terms, eitherof the terms, or both terms. It is also to be understood that theterminology employed in the Detailed Description sections of thisapplication is for the purpose of describing particular embodiments. Itis also contemplated that any optional feature of the inventivevariations described herein may be set forth and claimed independently,or in combination with any one or more of the features described herein.Moreover, in interpreting the disclosure, all terms should beinterpreted in the broadest possible manner consistent with the contextof the disclosed technology. In particular, the terms “comprises” and“comprising” should be interpreted as referring to elements, components,or steps in a non-exclusive manner, indicating that the referencedelements, components, or steps may be present, or utilized, or combinedwith other elements, components, or steps that are not expresslyreferenced.

Thus, specific compositions and methods of “Multiple-ComponentPharmaceutical Formulations And Methods For Their Use In TreatingNeuropathology And Neurodegeneration Caused By Traumatic Injury” havebeen disclosed and exemplified. It should be apparent, however, to thoseskilled in the art that many more variations, permutations andmodifications besides those already described are possible withoutdeparting from the inventive concepts herein, or from the spirit of theinvention. The inventive subject matter, therefore, is not to berestricted except in the spirit of the disclosure.

1. A formulation comprising A. at least one biologically active compoundselected from the group comprising anticonvulsants and antiepileptics;and B. at least one biologically active compound selected from the groupcomprising neurosteroids and neuroactive steroids.
 2. The formulation ofclaim 1, wherein the compound selected from the group comprisinganticonvulsants and antiepileptics is at least one form of gabapentin orpregabalin; and wherein the compound selected from the group comprisingneurosteroids and neuroactive steroids is at least one form ofprogesterone or synthetic progestin.
 3. The formulation of claim 1,wherein the at least one anticonvulsant or antiepileptic is one or morecompounds selected from the group consisting of gabapentin, pregabalin,barbiturates, benzodiazepines, bromides, carbamates, carboxamides, fattyacids, fructose derivatives, hydantoins, oxazolidinediones, propionates,pyrimidinediones, pyrrolidines, succinimides, sulphonamides, triazines,ureas and valproyamides and others known and unknown, as well as anyhomolog or derivative or compound acting on or through a receptor, anenzyme or other mechanism upon which an anticonvulsive/antiepileptic canact, as well as any compound acting on or through mechanisms that wouldmodify or affect in any way pathways or processes affected by one ormore anticonvulsant/antiepileptic compounds, as well as any relatedslow-release compound.
 4. The formulation of claim 1, wherein the atleast one neurosteroid or neuroactive steroid is one or more compoundsselected from the group consisting of progesterone, progesteroneprodrugs, progesterone derivatives, progesterone analogues, and otherprogesterone compounds such as but not exclusive to medroxyprogesteroneacetate, megestrol acetate, 17alpha-hydroxyprogesterone,5alpha-dihydroxyprogesterone, 3alpha,5alpha-trihydroxyprogesterone,14b-hydroxy progesterone, 17alpha-hydroxyprogesterone caproate,16-methyl-17-benzoyloxypregnen-4-en-3,20-dione,hydroxyprogesterone-3-O-carboxymethyloxime,21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone,17-p-bromopheny-lcarbamoyloxypregn-4-ene-3,20-dione,17-phenylcarbamoyl-oxypregn-4-ene-3,20-dione, 4-pregnene-3,20-dione,6,19-methanoprogesterone, 16,17-cyclohexano-4,5-dihydroprogesterone,nepapakistamine, vaganine D, Crinone, 18-oxo-18-vinylprogesterone,16,17-cyclopropanoprogesterone, caproxyprogesterone,21-hydroxy-6,19-oxidoprogesterone,17-acetoxy-9-fluoro-6-methylprogesterone, ZK 136798,3,17-dihydroxy-7-(4-methoxyphenyl)-androst-5-ene, 3,17-diacetate,progesterone-11HS-horseradish peroxidase,21-hydroxy-11,19-oxidopregn-4-ene-3,20-dione,21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione, 4-cyanoprogesterone,11,19-oxidoprogesterone, 6-fluoroprogesterone,2-hydroxy-4-pregnene-3,20-dione, progesterone-3-(O-carboxymethyloxime)-horseradish peroxidase, progesterone-11-hemisuccinyl-bovine serumalbumin, pentarane B, pentarane A, progesterone 6-hemimaleate,progesterone 6-hemisuccinate, 7-(carboxyethylthio)progesterone,progesterone 3-(O-carboxymethyl)oxime-bovine serum albumin,18-ethynylprogesterone, 18-vinylprogesterone,6-methylprogesteron-17-pivalate, progesterone-11-bovine serum albumin,allylestriol, progesterone-3-ethanolimine,3,20-dioxopregn-4-ene-18′-carboxaldehyde cyclic18′-(1,2-ethandiylmercaptal), 18-ethylenedithioprogesterone,17-acetoxy-6,16-dimethylene-4-pregnene-3,20-dione,17-hydroxy-6-dehydroprogesterone,2′-methyl-16,17-cyclohexaneprogesterone, 21,21-dichloroprogesterone,hydroxyprogesterone hemisuccinate bovine serum albumintetramethylrhodamine isothiocyanate,11-progesteryl-2-carboxymethyltyramine-4-(10-methyl)acridinium-9-carboxylate,progesterone 12-succinyltyrosine methyl ester, progesterone11-succinyltyrosine methyl ester,11-progesteryl-2-succinoyltyramine-4-(10-methyl)acridinium-9-carboxylate,2-hydroxymethyleneprogesterone, 2-cyanoprogesterone,17-(phenylseleno)progesterone, 21-(phenylseleno)progesterone and othersknown and unknown, and include other neurosteroids or neuroactivesteroids such as, but not exclusive to neuroactive progestagens(including but not limited to pregnenolone(3beta-hydroxypregn-5-en-20-one), 17-hydroxypregnenolone, progesterone,17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione,deoxycorticosterone, 11-deoxycortisol, 3 alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), 3 alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydroDOC)), neuroactive androgens(including but not limited to androstenedione (the precursor of3alpha,5alpha-A, or androsterone), androsterone(5alpha-androstan-3alpha-ol-17-one; 3alpha,5alpha-A),5alpha-dihydrotestosterone (5alpha-DHT) and its metabolite5alpha-androstane-3alpha,17beta-diol (3alpha,5alpha-Adiol),3α,17β-dihydroxy-5α-androstane, 3α-hydroxy-5α-androstan-17-one,3α-hydroxy-5β-androstan-17-one, androst-5-ene-3β,17β-diol,3β,17α-dihydroxy-pregn-5-en-20-one (17α-hydroxy-pregnenolone),3β-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA),testosterone, androst-4-ene-3,17-dione (androstenedione)), neuroactiveestrogens (including but not limited to estradiol, 17β-estradiol (βE2),17α-estradiol (αE2), estrone (E1) and estriol (E3), and phytoestrogens),neuroactive glucocorticoids (including but not limited to prednisolone),other neuroactive steroids metabolically downstream from these principalneuroactive steroids including but not limited to allopregnanolone,allotetrahydrodeoxycorticosterone (THDOC), and dehydroepiandrosterone(DHEA), additional neuroactive steroids including other derivatives suchas estradiol benzoate, neurosteroids and neuroactive steroids including,but not limited to, prednisolone, methylprednisolone, alphaxalone,alphadolone, hydroxydone, minaxolone, ganaxolone, deoxycorticosterone, 3alpha-hydroxy-5-alpha-pregnan-one (allopregnanolone), 3alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydro), as well asmetabolites of neurosteroids and neuroactive steroids, and including anycorticoid, glucocorticoid, estrogen, estrogen compound, androgen orandrogen compound or any such compound acting on or through aprogesterone, corticosteroid, glucocorticoid, estrogen, androgen orother neurosteroid or neuroactive steroid receptor or through any othermechanism upon which progesterone, a corticosteroid, a glucocorticoid,an estrogen or other neurosteroid or neuroactive steroid does or canact, as well as any homolog or derivative or compound acting on orthrough mechanisms that would modify, modulate or affect in any waypathways or processes affected by progesterone, estrogen or anyneurosteroid or neuroactive steroid, as well as any related slow-releasecompound.
 5. The formulation of claim 1, wherein the formulation is in aform and a dosage with respect to each of its components such that it isadapted and arranged for administration to a mammal, especially a human,in need thereof, such that the development, or the risk of development,of neuropathology is reduced, lessened, attenuated or prevented.
 6. Theformulation of claim 4, wherein the at least one form of gabapentin isprovided in a dosage range of from about 5.0 mg to about 9,600 mg, theat least one form of pregabalin is provided in a dosage range of fromabout 0.05 mg to about 2,400 mg and wherein the at least one form ofprogesterone or synthetic progestin is provided in a dosage range offrom about 0.05 mg to about 1,200 mg.
 7. The formulation of claim 1,wherein the formulation comprises a single dosage unit adapted andarranged to be administered a plurality of times of one or more dosageunits per day
 8. The formulation of claim 1, wherein one or more of thecompounds is in the form of one or more of salts, prodrugs, hydrates,derivatives or metabolites of the compound itself, analogs, homologs,compounds acting on or through mechanisms that compounds can act on orthrough or compounds that modify, modulate or affect in any way pathwaysor processes affected by compounds or formulations of the invention. 9.The formulation of claim 1, wherein A. the anticonvulsant orantiepileptic is at least one form of pregabalin; and B. wherein theneurosteroid or neuroactive steroid is at least one form ofprogesterone.
 10. The formulation of claim 1, wherein A. theanticonvulsant or antiepileptic is at least one form of gabapentin; andB. the neurosteroid or neuroactive steroid is at least one form ofsynthetic progestin.
 11. The formulation of claim 1, wherein A. theanticonvulsant or antiepileptic is at least one form of pregabalin; andB. the neurosteroid or neuroactive steroid is at least one form ofsynthetic progestin.
 12. The formulation of claim 1, wherein A. theanticonvulsant or antiepileptic is at least one form of gabapentin; andB. wherein the neurosteroid or neuroactive steroid is at least one formof progesterone.
 13. The formulation of claim 1, wherein the formulationis adapted and arranged to be administered with respect to time inrelation to i.) the onset of the trauma, ii.) in anticipation of apossible or potential trauma, iii.) during the trauma, and iv.) during aperiod of recovery from the trauma.
 14. A method for using theformulation of claim 1 for one or more of preventing, reducing theeffects of, or reducing the risk of development of, neuropathologyincident to trauma, the method comprising the steps or actions of A.providing the formulation of claim 1, wherein the formulation is adaptedfor the prevention of the development of neuropathology, wherein theformulation comprises two biologically active compounds in amounts thatare pharmaceutically effective for each compound, respectively, whenadministered in combination with the other biologically active compound,the two compounds respectively comprising a pharmaceutically effectiveamount of: i. at least one biologically active compound from the groupcomprising anticonvulsants and antiepileptics; ii. at least onebiologically active compound from the group comprising neurosteroids andneuroactive steroids; wherein the formulation is in a form adapted andarranged for administration to a mammal in need thereof, such that thedevelopment, or the risk of development, of neuropathology is reduced,lessened, attenuated or prevented, and B. administering the formulationof claim 1 to a mammal in need thereof.
 15. The method of claim 14,wherein Step B is effected with respect to time in relation to i.) theonset of the trauma, ii.) in anticipation of a possible or potentialtrauma, iii,) during the trauma, and iv.) during a period of recoveryfrom the trauma.
 16. The method of claim 14, wherein the compoundselected from the group comprising anticonvulsants and antiepileptics isat least one form of gabapentin or pregabalin; and wherein the compoundselected from the group comprising neurosteroids and neuroactivesteroids is at least one form of progesterone or synthetic progestin.17. The method of claim 14, wherein the formulation is adapted andarranged to be first administered within two hours after the trauma. 18.The method of claim 14, wherein the formulation is adapted and arrangedto be first administered as a single dosage unit within 24 hours afterthe onset of the trauma.
 19. The method of claim 14, wherein theformulation is adapted and arranged to be first administeredpreventively or prophylactically within 6 hours before the expectedonset of the trauma as a single dosage unit.
 20. The method of claim 14,wherein the formulation is adapted and arranged to be administeredadditionally one or a plurality of times after the formulation is firstadministered.
 21. A method for the treatment of preventing thedevelopment of neuropathology or neurodegeneration, and for theamelioration of the effects caused by trauma to a subject, theformulation comprising two biologically active compounds in amounts thatare pharmaceutically effective for each compound, respectively, whenadministered in combination with the other biologically active compound,the formulation comprising a pharmaceutically effective amount of thetwo biologically active compounds, for preventing, reducing the effectsof, and reducing the risk of development of, neuropathology andneurodegeneration incident to trauma, the method comprising the stepsand actions of A. providing a formulation adapted for the prevention ofthe development of neuropathology or neurodegeneration, wherein theformulation comprises two biologically active compounds in amounts thatare pharmaceutically effective for each compound, respectively, whenadministered in combination with the other biologically active compound,the two compounds respectively comprising a pharmaceutically effectiveamount of: i. at least one biologically active compound from the groupcomprising anticonvulsants and antiepileptic drugs; and ii. at least onebiologically active compound from the group comprising neurosteroids andneuroactive steroids; wherein the formulation is in a form and a dosagewith respect to each of its components such that it is adapted andarranged for administration to a mammal in need thereof, and such thatthe development, or the risk of development, of neuropathology orneurodegeneration is reduced, lessened, attenuated or prevented, and B.administering the formulation to a mammal in need thereof.
 22. Themethod of claim 21, wherein the compound selected from the group ofanticonvulsants and antiepileptics is at least one form of gabapentin orpregabalin, or at least one form of a pharmaceutically acceptable salt,ester or prodrug of gabapentin pregabalin.
 23. The method of claim 21,wherein the compound selected from the group of neurosteroids andneuroactive steroids is at least one form of progesterone or syntheticprogestin or at least one form of a pharmaceutically acceptable salt,ester or prodrug thereof.
 24. The method of claim 22, wherein thegabapentin or the at least one form of the pharmaceutically acceptablesalt, ester or prodrug thereof, is administered in a dosage rangeselected from the ranges of (i) from about 5.0 mg to about 9,600 mg,(ii) from about 50 mg to about 4,800 mg, (iii) from about 100 mg toabout 2,400 mg, and (iv) from about 200 mg to about 600 mg.
 25. Themethod of claim 22, herein the pregabalin or the at least one form ofthe pharmaceutically acceptable salt, ester or prodrug thereof, isadministered in a dosage range selected from the ranges of (1) fromabout 0.5 mg to about 2,400 mg, (ii) from about 15 mg to about 1,200 mg,(iii) from about 25 mg to about 600 mg, and (iv) from about 50 mg toabout 150 mg.
 26. The method of claim 23, wherein the progesterone orsynthetic progestin, or the at least one form of the pharmaceuticallyacceptable salt, ester or prodrug thereof, is administered in a dosagerange selected from the ranges of (i) from about 0.05 mg to about 1,200mg, (ii) from about 5 mg to about 600 mg, (iii) from about 50 mg toabout 450 mg, and (iv) from about 100 mg to about 300 mg.
 27. The methodof claim 21, wherein the neuropathology or neurodegeneration in asubject is selected from the group consisting of damage, injury, harm,loss, change in structure, change in phenotype, change in geneexpression, change in function or survival of nerves, nerve cells,neural support cells or neural support tissue that occurs after atraumatic event and develops over the seconds, minutes, hours, days,weeks or months following such an event and results from biochemicalcascades of cellular and metabolic processes that are activated ortriggered by the trauma-induced direct tissue damage and wherein damageis considered to involve endogenous processes or biosynthetic pathwaysthat govern, regulate or influence the structure, health, function, geneexpression or survival of nerves or nerve cells, or cells or tissuesupon which nerves or nerve cells depend to maintain health and function,such as neural support cells and neural support tissues and whereinneuropathology is selected from the group consisting of traumatic braininjury and ischemia, spinal cord neuropathology includes compression,vertebral collapse, cutting wounds, puncture wounds and ischemia,enteric nervous system neuropathology includes damage or injury toenteric nerve cells, progenitor cells, glial cells, interstitial cellsof Cajal and cells and tissues upon which normal function and health aredependent, injury to the enteric nervous system includes that resultingfrom chemotherapy, radiation therapy, ischemia, chemical andinflammatory trauma, physical trauma such as puncture wounds, parasiticand amoeboid infection, burns to the body, among other types of trauma,and peripheral nervous system neuropathology includes damage or injuryto nerve cells, nerve roots, ganglia, plexi, autonomic nerves or nervecells, sensory nerves or nerve cells, motor nerves or nerve cells, andto neural support cells or neural support tissues upon which nerve cellsdepend for normal function and health.
 28. The method of claim 21,wherein the trauma to a subject consists of one or more of traumaselected from the group consisting of that induced by vehicle accidents,workplace accidents, sports accidents, falls, burns, radiation,battlefield injuries such as but not exclusive to concussive blastinjuries and injuries from landmines or improvised explosive devices(IED's), and penetrating injuries.
 29. The method of claim 21, whereinthe effects caused by trauma to a subject consists of one or more ofprocesses and mechanisms selected from the group consisting of thosethat promote or interfere with at least one or more parts of processesthat are activated, induced or enhanced by trauma and that are involvedin maintaining or damaging nerves or nerve cells, or cells upon whichthe health or function of nerves, nerve cells, neural support cells orneural support tissues, or cells or tissues upon which neuron cellfunction depends.
 30. The method of claim 21, wherein the neuropathologyor neurodegeneration in a subject is caused by trauma selected from thegroup consisting of one or more of a wound, injury or damage to amammalian body or body part, or a condition resulting from such a woundor injury including physical, chemical, metabolic, medical or surgicalinjury or damage to any tissue nerve or nerve cell, whether in thecentral nervous system or in the periphery and wherein a chemical traumais selected from the group consisting of medication or medicationoverdose, drug or drug overdose, drug abuse (such asmethylenedioxyamphetamine, or MDMA, and the like), alcohol overdose,stimulant drugs such as pentylenetetrazol, carbon dioxide poisoning,heavy metals, acrylamide and related chemicals, overexposure to certainenvironmental chemicals such as copper or natural hazards such asscorpion venom toxin, herbicides, agricultural insecticides such aslindane, hazardous industrial chemicals, neurotoxin bioterrorismchemicals such as soman and sarin, radiation bioterrorism chemicals suchas polonium and strontium, and wherein metabolic trauma is selected fromthe group consisting of hypoxia, central nervous system ischemia,peripheral ischemia, enteric nervous system ischemia, hypoperfusion ofnerve tissue, multiple sclerosis, shingles (herpes zoster), diabetes,diabetic shock, stroke, epileptic or other seizure, post-polio syndrome,HIV/AIDS peripheral neuropathic pain, subacute posttraumatic myelopathy,and other effects, syndromes and conditions following some type oftrauma to the body or its nervous system, and wherein metabolic traumacan also include but is not exclusive to hypoglycemia, hyperglycemia,ischemia, diabetic shock, epilepsy or other seizure, hypoperfusion ofnerve tissue during cardiac arrest, hypoperfusion in newborns resultingfrom complications at delivery, and wherein the trauma induced bymedical treatment and procedure is selected from the group consisting ofone or more of injections, inoculation, implants, antibiotics, biologicdrugs, antibodies, chemotherapy, radiation therapy, immunosuppressants,during a medical procedure that can reduce or impede the blood supplyfor any period of time, and whereas trauma from surgery includeslaparoscopy, amputation, mastectomy, cesarean section, cardiac surgery,hernia repair, cholecystectomy, joint replacement, thoracotomy,reparative surgery, any case, condition and situation where there isdetectable or undetectable cut, wound, injury or damage to nerves, nervecells, neural support cells or neural support tissues, and wherelong-term outcome from surgery can include adverse health conditions anddisability as with failed back syndrome.
 31. The method of claim 27,wherein the neural support cell is selected from the group consisting ofcells that support and could be considered to support the health, normalfunction and survival of nerves and nerve cells, and include glialcells, microglia, myelin cells and satellite cells, astroglia,oligodendrocytes, satellite cells, Schwann cells, vascular endothelialcells, gastric epithelial cells, and interstitial cells of Cajal. 32.The method of claim 27, wherein the neural support tissue is selectedfrom the group consisting of tissue that supports the health, normalfunction, phenotype, gene expression or survival of nerves, nerve cellsor support cells, the group also consisting of cells of the vasculatureor microvasculature, particularly the endothelial cells that preventblood from leaking into nerve tissue and that provide the selectiveblood-nerve and blood-brain barrier that allows the passage of certainsupportive chemicals into nerve tissue as well as the passage of nervetissue wastes out of nerve tissue, as well as epithelial cells andinterstitial cells of Cajal of the gut.
 33. The method of claim 21,wherein the pharmaceutically effective amount is selected from the groupof one or more chemical entities that will alter, modify or promoteadaptive responses to trauma or interfere with, lessen or inhibitmaladaptive processes, for example by binding to an enzyme, receptor,allosteric site or other step of an endogenous biochemical, metabolic orbiosynthetic pathway to the extent that the effective functioning ofsuch pathway is altered, enabled, allowed or facilitated, as in the caseof adaptive processes, or would prevent, inhibit or lessen its effectivefunctioning, as in the case of maladaptive processes.
 34. The method ofclaim 21, wherein the administration of the pharmaceutically effectiveamounts of the biologically active compounds or pharmaceuticallyacceptable salts, esters or prodrugs thereof to a subject in needthereof, is one or more selected from the group consisting of oral,buccal, mucosal, parenteral, rectal, sub-cutaneous, transdermal,topical, intravenous, intrathecal, intravaginal, nasal, nasalinhalation, pulmonary inhalation, iontophoresis through the skin,iontophoresis through mucosal or buccal membranes, dermal patch,epidural, intracranial, intrapharyngeal, sublingual, intra-articular,intramuscular and subcutaneous.
 35. The method of claim 21, wherein theform of the pharmaceutically effective amounts of biologically activecompounds to be administered is one or more of pharmaceuticallyacceptable salts, esters or prodrugs thereof, excipients, penetrationenhancers, stabilizers, absorption enhancers and carriers is selectedfrom the group consisting of a pharmaceutically acceptable substancethat assists or enhances the delivery or effectiveness of the compoundor compounds of invention embodiments
 36. The method of claim 21,wherein the formulation is administered additionally one, or a pluralityof, times after the formulation is first administered.
 37. The method ofclaim 21, wherein the formulation is administered one, or a plurality oftimes as a sustaining dose.
 38. The method of claim 21, wherein saidmethod is commenced at a time selected from the group consisting of oneor more of (i) one month after the trauma, (ii) one week after thetrauma, (iii) one day after the trauma, (iv) less than one day after thetrauma, (v) less than 18 hours after the trauma, (vi) less than twelvehours after the trauma, (vii) less than six hours after the trauma and(viii) less than one hour after the trauma.
 39. The method of claim 21,wherein the method is commenced as a prophylactic step at a time periodbefore a possible trauma selected from the group consisting of one ormore of (i) less than one hour before the possible trauma, (ii) lessthan six hours before the possible trauma and (iii) less thantwenty-four hours before the possible trauma.
 40. The method of claim21, wherein the method is commenced as a preventive step at a timeselected from the group consisting of one or more of (i) less than onehour before the trauma, (ii) less than six hours before the trauma, and(iii) less than twenty-four hours before the trauma.